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  • Loss of BAP1 expression is associated with an immunosuppressivemicroenvironment in uveal melanoma, with implications for immunotherapy development
    J. Pathol. (IF 5.942) Pub Date : 2020-01-20
    Carlos R. Figueiredo; Helen Kalirai; Joseph J. Sacco; Ricardo A. Azevedo; Andrew Duckworth; Joseph R. Slupsky; Judy M. Coulson; Sarah E. Coupland

    Immunotherapy using immune checkpoint inhibitors (ICIs) induces durable responses in many metastatic cancers. Metastatic uveal melanoma (mUM), typically occurring in the liver, is one of the most refractory tumours to ICIs and has dismal outcomes. Monosomy 3 (M3), polysomy 8q and BAP1 loss in primary uveal melanoma (pUM) are associated with poor prognoses. The presence of tumour infiltrating lymphocytes (TILs) within pUM and surrounding mUM ‐ and some evidence of clinical responses to adoptive TIL transfer ‐ strongly suggest that UM are indeed immunogenic despite their low mutational burden. The mechanisms that suppress TILs in pUM and mUM are unknown. We show that BAP1 loss is correlated with upregulation of several genes associated with suppressive immune responses, some of which build an immune suppressive axis, including HLA‐DR, CD38, and CD74. Further, single‐cell analysis of pUM by mass cytometry confirmed the expression of these and other markers revealing important functions of infiltrating immune cells in UM, most being a regulatory CD8+ T lymphocytes and tumour associated macrophages (TAMs). Transcriptomic analysis of hepatic mUM revealed similar immune profiles to pUM with BAP1 loss, including the expression of IDO1. At the protein level, we observed TAMs and TILs entrapped within peritumoral fibrotic areas surrounding mUM, with increased expression of IDO1, PD‐L1 and β‐catenin (CTNNB1), suggesting tumour‐driven immune exclusion and hence the immunotherapy resistance. These findings aid the understanding of how the immune response is organised in BAP1‐ mUM, which will further enable functional validation of detected biomarkers and the development of focused immunotherapeutic approaches.

    更新日期:2020-01-22
  • Loss of GATA4 causes ectopic pancreas in the stomach
    J. Pathol. (IF 5.942) Pub Date : 2020-01-20
    Elisa Rodríguez‐Seguel; Laura Villamayor; Noelia Arroyo; Mónica P De Andrés; Francisco X Real; Franz Martín; David A Cano; Anabel Rojas

    Pancreatic heterotopia is defined as pancreatic tissue outside its normal location in the body and anatomically separated from the pancreas. In this work we have analyzed the stomach glandular epithelium of Gata4 flox/flox; Pdx1‐Cre mice (Gata4KO mice). We found that Gata4KO glandular epithelium displays an atypical morphology similar to the cornified squamous epithelium and exhibits upregulation of forestomach markers. The developing gastric units fail to form properly, and the glandular epithelial cells do not express markers of gastric gland in the absence of GATA4. Of interest, the developing glands of the Gata4KO stomach express pancreatic cell markers. Furthermore, a mass of pancreatic tissue located in the subserosa of the Gata4KO stomach is observed at adult stages. Heterotopic pancreas found in Gata4‐deficient mice contains all three pancreatic cell lineages: ductal, acinar, and endocrine. Moreover, Gata4 expression is downregulated in ectopic pancreatic tissue of some human biopsy samples. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2020-01-21
  • Angioimmunoblastic T‐cell lymphoma contains multiple clonal T‐cell populations derived from a common TET2 mutant progenitor cell
    J. Pathol. (IF 5.942) Pub Date : 2020-01-16
    Wen‐Qing Yao; Fangtian Wu; Wenyan Zhang; Shih‐Sung Chuang; Joe S Thompson; Zi Chen; Shao‐Wei Zhang; Alexandra Clipson; Ming Wang; Hongxiang Liu; Hani Bibawi; Yuanxue Huang; Luis Campos; John W Grant; Penny Wright; Hesham EI‐Daly; Lívia Rásó‐Barnett; Lorant Farkas; George A Follows; Zifen Gao; Ayoma D Attygalle; Margaret Ashton‐Key; Weiping Liu; Ming‐Qing Du

    Angioimmunoblastic T‐cell lymphoma (AITL) is a neoplastic proliferation of T follicular helper cells with clinical and histological presentations suggesting a role of antigenic drive in its development. Genetically, it is characterized by a stepwise acquisition of somatic mutations, with early mutations involving epigenetic regulators (TET2, DNMT3A) and occurring in haematopoietic stem cells, with subsequent changes involving signaling molecules (RHOA, VAV1, PLCG1, CD28) critical for T‐cell biology. To search for evidence of potential oncogenic cooperation between genetic changes and intrinsic T cell receptor (TCR) signaling, we investigated somatic mutations and T‐cell receptor β (TRB) rearrangement in 119 AITL, 11 peripheral T‐cell lymphomas with T follicular helper phenotype (PTCL‐TFH), and 25 PTCL‐NOS using Fluidigm polymerase chain reaction (PCR) and Illumina MiSeq sequencing. We confirmed frequent TET2, DNMT3A, and RHOA mutations in AITL (72%, 34%, 61%) and PTCL‐TFH (73%, 36%, 45%) and showed multiple TET2 mutations (2 or 3) in 57% of the involved AITL and PTCL‐TFH. Clonal TRB rearrangement was seen in 76 cases with multiple functional rearrangements (2–4) in 18 cases (24%). In selected cases, we confirmed bi‐clonal T‐cell populations and further demonstrated that these independent T‐cell populations harboured identical TET2 mutations by using BaseScope in situ hybridization, suggesting their derivation from a common TET2 mutant progenitor cell population. Furthermore, both T‐cell populations expressed CD4. Finally, in comparison with tonsillar TFH cells, both AITL and PTCL‐TFH showed a significant overrepresentation of several TRB variable family members, particularly TRBV19*01. Our findings suggest the presence of parallel neoplastic evolutions from a common TET2 mutant haematopoietic progenitor pool in AITL and PTCL‐TFH, albeit to be confirmed in a large series of cases. The biased TRBV usage in these lymphomas suggests that antigenic stimulation may play an important role in predilection of T cells to clonal expansion and malignant transformation. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

    更新日期:2020-01-17
  • Immunoproteasome subunit β5i regulates diet‐induced atherosclerosis through altering MERTK‐mediated efferocytosis in Apoe knockout mice
    J. Pathol. (IF 5.942) Pub Date : 2020-01-14
    Jiawei Liao; Yunpeng Xie; Qiuyue Lin; Xiaolei Yang; Xiangbo An; Yunlong Xia; Jie Du; Feng Wang; Hui‐Hua Li

    The immunoproteasome contains three catalytic subunits (β1i, β2i and β5i) that are important modulators of immune cell homeostasis. A previous study showed a correlation between β5i and human atherosclerotic plaque instability; however, the causative role of β5i in atherosclerosis and the underlying mechanisms remain unknown. Here we explored this issue in apolipoprotein E (Apoe) knockout (eKO) mice with genetic deletion or pharmacological inhibition of β5i. We found that β5i expression was upregulated in lesional macrophages after an atherogenic diet (ATD). β5i/Apoe double KO (dKO) mice fed on the ATD had a significant decrease in both lesion area and necrotic core area, compared with eKO controls. Moreover, dKO mice had less caspase‐3+ apoptotic cell accumulation but enhanced efferocytosis of apoptotic cells and increased expression of Mer receptor tyrosine kinase (MERTK). Consistently, similar phenotypes were observed in eKO mice transplanted with dKO bone marrow or treated with β5i‐specific inhibitor PR‐957. Mechanistic studies in vitro revealed that β5i deletion reduced IκBα degradation and inhibited NF‐κB activation, promoting Mertk transcription and efferocytosis, thereby attenuating apoptotic cell accumulation. In conclusion, we demonstrate that β5i plays an important role in diet‐induced atherosclerosis by altering MERTK‐mediated efferocytosis. β5i might be a potential pharmaceutical target against atherosclerosis. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2020-01-14
  • Negative regulation of dendritic cell activation in psoriasis mediated via CD100‐Plexin‐B2
    J. Pathol. (IF 5.942) Pub Date : 2020-01-14
    Chunying Xiao; Yang Luo; Chen Zhang; Zhenlai Zhu; Luting Yang; Hongjiang Qiao; Meng Fu; Gang Wang; Xu Yao; Wei Li

    Psoriasis is a chronic inflammatory skin disease, in which dendritic cells (DCs) play a pivotal role by inducing Th1/Th17 immune responses; however, the regulation of DCs activation in psoriasis remains largely unknown. Previously we found that the level of soluble CD100 was increased in sera of psoriasis patients, and CD100 promoted the activation of inflammasome in keratinocytes. In the present study, CD100 knockout mice were utilized for generation of imiquimod (IMQ)‐induced psoriatic dermatitis, with the result that skin inflammation in the early, but not late, phase of the psoriatic dermatitis was significantly exacerbated compared to that in wild‐type controls. This was attributed mainly to the deficiency of CD100 in hematopoietic cells. Bone marrow‐derived DCs, but not T cells or keratinocytes, from CD100 knockout mice produced significantly increased levels of IL‐1β, IL‐36 and IL‐23 upon stimulation with IMQ in a Plexin‐B2‐dependent manner. Moreover, the surface level of Plexin‐B2 on DCs of psoriasis patients was lower than that of healthy individuals, and CD100 attenuated IMQ‐induced production of IL‐1β and IL‐36 from monocyte‐derived DCs of psoriasis patients. Our results uncovered a negative regulatory mechanism for DCs activation in psoriasis, which was mediated via CD100‐Plexin‐B2 in a cell type‐ and receptor‐ specific manner.

    更新日期:2020-01-14
  • Proteins in stool as biomarkers for non‐invasive detection of colorectal adenomas with high risk of progression
    J. Pathol. (IF 5.942) Pub Date : 2020-01-13
    Malgorzata A Komor; Linda JW Bosch; Veerle MH Coupé; Christian Rausch; Thang V Pham; Sander R Piersma; Sandra Mongera; Chris JJ Mulder; Evelien Dekker; Ernst J Kuipers; Mark A van de Wiel; Beatriz Carvalho; Remond JA Fijneman; Connie R Jimenez; Gerrit A Meijer; Meike de Wit

    Screening to detect colorectal cancer (CRC) in an early or premalignant state is an effective method to reduce CRC mortality rates. Current stool‐based screening tests, e.g. fecal immunochemical test (FIT), have a suboptimal sensitivity for colorectal adenomas and difficulty distinguishing adenomas at high risk of progressing to cancer from those at lower risk. We aimed to identify stool protein biomarker panels that can be used for the early detection of high‐risk adenomas and CRC. Proteomics data (LC–MS/MS) were collected on stool samples from adenoma (n = 71) and CRC patients (n = 81) as well as controls (n = 129). Colorectal adenoma tissue samples were characterized by low‐coverage whole‐genome sequencing to determine their risk of progression based on specific DNA copy number changes. Proteomics data were used for logistic regression modeling to establish protein biomarker panels. In total, 15 of the adenomas (15.8%) were defined as high risk of progressing to cancer. A protein panel, consisting of haptoglobin (Hp), LAMP1, SYNE2, and ANXA6, was identified for the detection of high‐risk adenomas (sensitivity of 53% at specificity of 95%). Two panels, one consisting of Hp and LRG1 and one of Hp, LRG1, RBP4, and FN1, were identified for high‐risk adenomas and CRCs detection (sensitivity of 66% and 62%, respectively, at specificity of 95%). Validation of Hp as a biomarker for high‐risk adenomas and CRCs was performed using an antibody‐based assay in FIT samples from a subset of individuals from the discovery series (n = 158) and an independent validation series (n = 795). Hp protein was significantly more abundant in high‐risk adenoma FIT samples compared to controls in the discovery (p = 0.036) and the validation series (p = 9e‐5). We conclude that Hp, LAMP1, SYNE2, LRG1, RBP4, FN1, and ANXA6 may be of value as stool biomarkers for early detection of high‐risk adenomas and CRCs. © 2019 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

    更新日期:2020-01-13
  • Upregulation of Cisd2 attenuates Alzheimer's‐related neuronal loss in mice
    J. Pathol. (IF 5.942) Pub Date : 2020-01-13
    Yi‐Fan Chen; Tzu‐Yu Chou; I‐Hsuan Lin; Chung‐Guang Chen; Cheng‐Heng Kao; Guo‐Jen Huang; Liang‐Kung Chen; Pei‐Ning Wang; Ching‐Po Lin; Ting‐Fen Tsai

    CDGSH iron–sulfur domain‐containing protein 2 (Cisd2), a protein that declines in an age‐dependent manner, mediates lifespan in mammals. Cisd2 deficiency causes accelerated aging and shortened lifespan, whereas persistent expression of Cisd2 promotes longevity in mice. Alzheimer's disease (AD) is the most prevalent form of senile dementia and is without an effective therapeutic strategy. We investigated whether Cisd2 upregulation is able to ameliorate amyloid β (Aβ) toxicity and prevent neuronal loss using an AD mouse model. Our study makes three major discoveries. First, using the AD mouse model (APP/PS1 double transgenic mice), the dosage of Cisd2 appears to modulate the severity of AD phenotypes. Cisd2 overexpression (∼two‐fold) significantly promoted survival and alleviated the pathological defects associated with AD. Conversely, Cisd2 deficiency accelerated AD pathogenesis. Secondly, Cisd2 overexpression protected against Aβ‐mediated mitochondrial damage and attenuated loss of neurons and neuronal progenitor cells. Finally, an increase in Cisd2 shifted the expression profiles of a panel of genes that are dysregulated by AD toward the patterns observed in wild‐type mice. These findings highlight Cisd2‐based therapies as a potential disease‐modifying strategy for AD. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

    更新日期:2020-01-13
  • Inhibition of tissue non‐specific alkaline phosphatase, a novel therapy against arterial media calcification?
    J. Pathol. (IF 5.942) Pub Date : 2020-01-12
    Britt Opdebeeck; Patrick C D'Haese; Anja Verhulst

    Arterial media calcification refers to ectopic mineralization in the arterial wall and favors arterial stiffness and cardiovascular events. Patients with chronic kidney disease (CKD), diabetes, or osteoporosis are highly vulnerable to the development of arterial media calcifications. Tissue non‐specific alkaline phosphatase (TNAP) is upregulated in calcified arteries and plays a key role in the degradation of the calcification inhibitor pyrophosphate into inorganic phosphate ions. A recent study published in The Journal of Pathology showed that an oral dosage of 10 or 30 mg/kg/day SBI‐425, a selective TNAP inhibitor, inhibited the development of arterial media calcification in mice with CKD, without affecting bone mineralization. Their results indicated that SBI‐425 is an effective and safe treatment for arterial media calcification. However, additional studies regarding the effect of TNAP‐inhibitor SBI‐425 on the progression and even the reversion of pre‐existing pathological arterial media calcifications without affecting physiological bone mineralization are deserved. Furthermore, investigating the extent to which SBI‐425 inhibits arterial calcification in a non‐CKD context would be of particular interest to treat this comorbidity in diabetes and osteoporosis patients. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2020-01-13
  • Diabetic pre‐programming of myelopoiesis impairs tissue repair
    J. Pathol. (IF 5.942) Pub Date : 2020-01-12
    Yagna PR Jarajapu

    Bone marrow‐derived monocyte–macrophages promote healing of injured tissue cooperatively with vasculogenic hematopoietic stem/progenitor cells. However, diabetes dysregulates hematopoiesis and attenuates bone marrow‐derived tissue‐reparative responses. In a recent issue of The Journal of Pathology, Barman et al extensively characterized myelopoietic responses in bone marrow following skin wounding in a type 2 model of diabetes. The study demonstrated that accumulation of monocyte–macrophages in the peripheral tissues is increased due to diabetic myelopoiesis that would oppose the reparative process following tissue injury. Interestingly, in this model, pathological myelopoiesis is independent of IL‐1β. The potential prophylactic and therapeutic implications of these data are discussed in terms of paracrine signaling, macrophage polarization, and hematopoietic stem cell mobilization/retention. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2020-01-13
  • Clinicopathological and molecular characterisation of ‘multiple‐classifier’ endometrial carcinomas
    J. Pathol. (IF 5.942) Pub Date : 2020-01-12
    Alicia León‐Castillo; Ester Gilvazquez; Remi Nout; Vincent THBM Smit; Jessica N McAlpine; Melissa McConechy; Stefan Kommoss; Sara Y Brucker; Joseph W Carlson; Elisabeth Epstein; Tilman T Rau; Robert A Soslow; Raji Ganesan; Xavier Matias‐Guiu; Esther Oliva; Beth T Harrison; David N Church; C Blake Gilks; Tjalling Bosse

    Endometrial carcinoma (EC) molecular classification based on four molecular subclasses identified in The Cancer Genome Atlas (TCGA) has gained relevance in recent years due to its prognostic utility and potential to predict benefit from adjuvant treatment. While most ECs can be classified based on a single classifier (POLE exonuclease domain mutations – POLEmut, MMR deficiency – MMRd, p53 abnormal – p53abn), a small but clinically relevant group of tumours harbour more than one molecular classifying feature and are referred to as ‘multiple‐classifier’ ECs. We aimed to describe the clinicopathological and molecular features of multiple‐classifier ECs with abnormal p53 (p53abn). Within a cohort of 3518 molecularly profiled ECs, 107 (3%) tumours displayed p53abn in addition to another classifier(s), including 64 with MMRd (MMRd–p53abn), 31 with POLEmut (POLEmut–p53abn), and 12 with all three aberrations (MMRd–POLEmut–p53abn). MMRd–p53abn ECs and POLEmut–p53abn ECs were mostly grade 3 endometrioid ECs, early stage, and frequently showed morphological features characteristic of MMRd or POLEmut ECs. 18/28 (60%) MMRd–p53abn ECs and 7/15 (46.7%) POLEmut–p53abn ECs showed subclonal p53 overexpression, suggesting that TP53 mutation was a secondary event acquired during tumour progression. Hierarchical clustering of TCGA ECs by single nucleotide variant (SNV) type and somatic copy number alterations (SCNAs) revealed that MMRd–p53abn tumours mostly clustered with single‐classifier MMRd tumours (20/23) rather than single‐classifier p53abn tumours (3/23), while POLEmut–p53abn tumours mostly clustered with single‐classifier POLEmut tumours (12/13) and seldom with single‐classifier p53abn tumours (1/13) (both p ≤ 0.001, chi‐squared test). Finally, the clinical outcome of patients with MMRd–p53abn and POLEmut–p53abn ECs [stage I 5‐year recurrence‐free survival (RFS) of 92.2% and 94.1%, respectively] was significantly different from single‐classifier p53abn EC (stage I RFS 70.8%, p = 0.024 and p = 0.050, respectively). Our results support the classification of MMRd–p53abn EC as MMRd and POLEmut–p53abn EC as POLEmut. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

    更新日期:2020-01-13
  • Prekallikrein – an emerging therapeutic target for Klebsiella pneumoniae infection?
    J. Pathol. (IF 5.942) Pub Date : 2020-01-13
    Zena Lam; Alison M Condliffe

    Klebsiella pneumoniae is a gram‐negative bacterium that is increasingly difficult to treat due to the emergence of multidrug resistant strains. In a recent article, Ding et al demonstrate that prekallikrein depletion in mice followed by intranasal instillation of K. pneumoniae leads to a reduced bacterial burden and prolonged host survival, together with evidence of reduced distant organ damage. These effects are apparently independent of the role of prekallikrein in the contact system, and are associated with transcriptional changes relevant to innate immunity in the lung, established prior to infection. This study highlights the importance of further investigating the role of prekallikrein and other contact cascade components in host defence to counter K. pneumoniae (and perhaps other pathogens), with an overall aim of identifying potential therapeutic targets relevant to pulmonary infection with such resistant pathogens.

    更新日期:2020-01-13
  • Hippo pathway effectors YAP1/TAZ induce an EWS‐FLI1‐opposing gene signature and associate with disease progression in Ewing sarcoma
    J. Pathol. (IF 5.942) Pub Date : 2019-12-27
    Pablo Rodríguez‐Núñez; Laura Romero‐Pérez; Ana T. Amaral; Pilar Puerto‐Camacho; Carmen Jordán; David Marcilla; Thomas G. P. Grünewald; Javier Alonso; Enrique de Alava; Juan Díaz‐Martín

    YAP1 and TAZ (WWTR1) oncoproteins are the final transducers of the Hippo tumor suppressor pathway. Deregulation of the pathway leads to YAP1/TAZ activation fostering tumorigenesis in multiple malignant tumor types, including sarcoma. However, oncogenic mutations within the core components of the Hippo pathway are uncommon. Ewing Sarcoma (EwS), a pediatric cancer with low mutation rate, is characterized by a canonical fusion involving the gene EWSR1, and FLI1 as the most common partner. The fusion protein is a potent driver of oncogenesis, but secondary alterations are scarce, and little is known about other biological factors that determine the risk of relapse or progression. We have observed YAP1/TAZ expression and transcriptional activity in EwS cell lines. Analyses of 55 primary human EwS samples revealed that high YAP1/TAZ expression was associated with progression of the disease and predicted poorer outcome. We did not observe recurrent SNV or copy number gains/losses in Hippo pathway‐related loci. However, differential CpG methylation of the RASSF1 locus (a regulator of Hippo pathway) was observed in EwS cell lines compared with mesenchymal stem cells, the putative cell of origin of EwS. Hypermethylation of RASSF1 correlated with the transcriptional silencing of the tumor suppressor isoform RASFF1A, and transcriptional activation of the pro‐tumorigenic isoform RASSF1C which promotes YAP1/TAZ activation. Knockdown of YAP1/TAZ decreased proliferation and invasion abilities of EwS cells and revealed that YAP1/TAZ transcription activity is inversely correlated with the EWS‐FLI1 transcriptional signature. This transcriptional antagonism could be explained partly by EWS‐FLI1‐mediated transcriptional repression of TAZ. Thus, YAP1/TAZ may override the transcriptional program induced by the fusion protein, contributing to the phenotypic plasticity determined by dynamic fluctuation of the fusion protein, a recently proposed model for disease dissemination in EwS.

    更新日期:2019-12-27
  • Association of autophagy status with amount of Fusobacterium nucleatum in colorectal cancer
    J. Pathol. (IF 5.942) Pub Date : 2019-12-27
    Koichiro Haruki; Keisuke Kosumi; Tsuyoshi Hamada; Tyler S. Twombly; Juha P. Väyrynen; Sun A. Kim; Yohei Masugi; Zhi Rong Qian; Kosuke Mima; Yoshifumi Baba; Annacarolina da Silva; Jennifer Borowsky; Kota Arima; Kenji Fujiyoshi; Mai Chan Lau; Peilong Li; Chunguang Guo; Yang Chen; Mingyang Song; Jonathan A. Nowak; Reiko Nishihara; Katsuhiko Yanaga; Xuehong Zhang; Kana Wu; Susan Bullman; Wendy S. Garrett; Curtis Huttenhower; Jeffrey A. Meyerhardt; Marios Giannakis; Andrew T. Chan; Charles S. Fuchs; Shuji Ogino

    Fusobacterium nucleatum (F. nucleatum), which has been associated with colorectal carcinogenesis, can impair anti‐tumour immunity, and actively invade colon epithelial cells. Considering the critical role of autophagy in host defence against microorganisms, we hypothesised that autophagic activity of tumour cells might influence the amount of F. nucleatum in colorectal cancer tissue. Using 724 rectal and colon cancer cases within the Nurses' Health Study and the Health Professionals Follow‐up Study, we evaluated autophagic activity of tumour cells by immunohistochemical analyses of BECN1 (beclin 1), MAP1LC3 (LC3), and SQSTM1 (p62) expression. We measured the amount of F. nucleatum DNA in tumour tissue by quantitative PCR. We conducted multivariable ordinal logistic regression analyses to examine the association of tumour BECN1, MAP1LC3, and SQSTM1 expression with the amount of F. nucleatum, adjusting for potential confounders, including microsatellite instability status, CpG island methylator phenotype, long‐interspersed nucleotide element‐1 methylation, and KRAS, BRAF and PIK3CA mutations. Compared with BECN1‐low cases, BECN1‐intermediate and BECN1‐high cases were associated with lower amounts of F. nucleatum with odds ratios (for a unit increase in three ordinal categories of the amount of F. nucleatum) of 0.54 (95% confidence interval, 0.29–0.99) and 0.31 (95% confidence interval, 0.16–0.60), respectively (Ptrend < 0.001 across ordinal BECN1 categories). Tumour MAP1LC3 and SQSTM1 levels were not significantly associated with the amount of F. nucleatum (Ptrend > 0.06). Tumour BECN1, MAP1LC3, and SQSTM1 levels were not significantly associated with patient survival (Ptrend > 0.10). In conclusion, tumour BECN1 expression is inversely associated with the amount of F. nucleatum in colorectal cancer tissue, suggesting a possible role of autophagy in the elimination of invasive microorganisms.

    更新日期:2019-12-27
  • Perivascular Neuropilin‐1 expression is an independent marker of improved survival in renal cell carcinoma
    J. Pathol. (IF 5.942) Pub Date : 2019-12-27
    Eric Morin; Cecilia Lindskog; Martin Johansson; Lars Egevad; Per Sandström; Ulrika Harmenberg; Lena Claesson‐Welsh; Elin Sjöberg

    Renal cell carcinoma (RCC) treatment has improved in the last decade with the introduction of drugs targeting tumor angiogenesis. However, the 5‐year survival of metastatic disease is still only 10–15%. Here, we explored the prognostic significance of compartment‐specific expression of Neuropilin 1 (NRP1), a co‐receptor for vascular endothelial growth factor (VEGF). NRP1 expression was analyzed in RCC tumor vessels, in perivascular tumor cells and generally in the tumor cell compartment. Moreover, complex formation between NRP1 and the main VEGF receptor, VEGFR2, was determined. Two RCC tissue microarrays were used; a discovery cohort consisting of 64 patients and a validation cohort of 314 patients. VEGFR2/NRP1 complex formation in cis (on the same cell) and trans (between cells) configurations was determined by in situ proximity ligation assay, and NRP1 protein expression in three compartments (endothelial cells, perivascular tumor cells and general tumor cell expression) was determined by immunofluorescent staining. Expression of NRP1 in perivascular tumor cells was explored as a marker for RCC survival in the two RCC cohorts. Results were further validated using a publicly available gene expression dataset of clear cell RCC. We found that VEGFR2/NRP1 trans complexes were detected in 75% of the patient samples. The presence of trans VEGFR2/NRP1 complexes or perivascular NRP1 expression was associated with a reduced tumor vessel density and size. When exploring NRP1 as a biomarker for RCC prognosis, perivascular NRP1 and general tumor cell NRP1 protein expression correlated with improved survival in the two independent cohorts, and significant results were obtained also at the mRNA level using the publicly available ccRCC gene expression dataset. Only perivascular NRP1 expression remained significant in multivariable analysis. Our work shows that perivascular NRP1 expression is an independent marker of improved survival in RCC patients, by forming VEGFR2/NRP1 complexes in trans with the tumor endothelium.

    更新日期:2019-12-27
  • Real‐time ex vivo perfusion of human lymph nodes invaded by cancer (REPLICANT): a feasibility study
    J. Pathol. (IF 5.942) Pub Date : 2019-12-22
    Rachel Barrow‐McGee; Julia Procter; Julie Owen; Natalie Woodman; Cristina Lombardelli; Ashutosh Kothari; Tibor Kovacs; Michael Douek; Simi George; Peter A Barry; Kelvin Ramsey; Amy Gibson; Richard Buus; Erle Holgersen; Rachael Natrajan; Syed Haider; Michael J Shattock; Cheryl Gillett; Andrew NJ Tutt; Sarah E Pinder; Kalnisha Naidoo

    Understanding how breast cancer (BC) grows in axillary lymph nodes (ALNs), and refining how therapies might halt that process, is clinically important. However, modelling the complex ALN microenvironment is difficult, and no human models exist at present. We harvested ALNs from ten BC patients, and perfused them at 37 °C ex vivo for up to 24 h. Controlled autologous testing showed that ALNs remain viable after 24 h of ex vivo perfusion: haematoxylin and eosin‐stained histological appearance and proliferation (by Ki67 immunohistochemistry) did not change significantly over time for any perfused ALN compared with a control from time‐point zero. Furthermore, targeted gene expression analysis (NanoString PanCancer IO360 panel) showed that only 21/750 genes were differentially expressed between control and perfused ALNs (|log2 FC| > 1 and q < 0.1): none were involved in apoptosis and metabolism, but rather all 21 genes were involved in immune function and angiogenesis. During perfusion, tissue acid–base balance remained stable. Interestingly, the flow rate increased (p < 0.001) in cancer‐replaced (i.e. metastasis occupied more than 90% of the surface area on multiple levels) compared to cancer‐free nodes (i.e. nodes with no metastasis on multiple sections). CXCL11 transcripts were significantly more abundant in cancer‐replaced nodes, while CXCL12 transcripts were significantly more abundant in cancer‐free nodes. These cytokines were also detected in the circulating perfusate. Monoclonal antibodies (nivolumab and trastuzumab) were administered into a further three ALNs to confirm perfusion efficacy. These drugs saturated the nodes; nivolumab even induced cancer cell death. Normothermic ALN perfusion is not only feasible but sustains the tumour microenvironment ex vivo for scientific investigation. This model could facilitate the identification of actionable immuno‐oncology targets. © 2019 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

    更新日期:2019-12-23
  • Mesenchymal stromal cells in cancer: a review of their immunomodulatory functions and dual effects on tumor progression
    J. Pathol. (IF 5.942) Pub Date : 2019-12-18
    Sabine Galland; Ivan Stamenkovic

    Mesenchymal stem or stromal cells (MSCs) are pluripotent cells implicated in a broad range of physiological events, including organogenesis and maintenance of tissue homeostasis as well as tissue regeneration and repair. Because their current definition is somewhat loose – based primarily on their ability to differentiate into a variety of mesenchymal tissues, adhere to plastic, and express, or lack, a handful of cell surface markers – MSCs likely encompass several subpopulations, which may have diverse properties. Their diversity may explain, at least in part, the pleiotropic functions that they display in different physiological and pathological settings. In the context of tissue injury, MSCs can respectively promote and attenuate inflammation during the early and late phases of tissue repair. They may thereby act as sensors of the inflammatory response and secrete mediators that boost or temper the response as required by the stage of the reparatory and regenerative process. MSCs are also implicated in regulating tumor development, in which they are increasingly recognized to play a complex role. Thus, MSCs can both promote and constrain tumor progression by directly affecting tumor cells via secreted mediators and cell–cell interactions and by modulating the innate and adaptive immune response. This review summarizes our current understanding of MSC involvement in tumor development and highlights the mechanistic underpinnings of their implication in tumor growth and progression. © 2019 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

    更新日期:2019-12-19
  • Making sense of giant cell lesions of the jaws (GCLJ): lessons learned from next‐generation sequencing
    J. Pathol. (IF 5.942) Pub Date : 2019-12-18
    Carolina C Gomes; Marina G Diniz; Victor C Bastos; Vanessa F Bernardes; Ricardo S Gomez

    Next‐generation sequencing has revealed mutations in several bone‐related lesions and was recently used to uncover the genetic basis of giant cell lesions of the jaws (GCLJ). Consistent with their benign nature, GCLJ show a low tumor mutation burden. They also harbor somatic, heterozygous, mutually exclusive mutations in TRPV4, KRAS, or FGFR1. These signature mutations occur only in a subset of lesional cells, suggesting the existence of a ‘landscaping effect’, with mutant cells inducing abnormal accumulation of non‐mutant cells that form the tumor mass. Osteoclast‐rich lesions with histological similarities to GCLJ can occur in the jaws sporadically or in association with genetically inherited syndromes. Based on recent results, the pathogenesis of a subgroup of sporadic GCLJ seems closely related to non‐ossifying fibroma of long bones, with both lesions sharing MAPK pathway‐activating mutations. In this review, we extrapolate from these recent findings to contextualize GCLJ genetics and we highlight the therapeutic implications of this new information. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-12-19
  • Proteome analysis of formalin‐fixed paraffin‐embedded colorectal adenomas reveals the heterogeneous nature of traditional serrated adenomas compared to other colorectal adenomas
    J. Pathol. (IF 5.942) Pub Date : 2019-12-15
    Pierre Sohier; Romain Sanson; Marjorie Leduc; Anne Audebourg; Cédric Broussard; Virginie Salnot; Pierre‐Alexandre Just; Eric Pasmant; Patrick Mayeux; François Guillonneau; Béatrice Romagnolo; Christine Perret; Benoît Terris

    Traditional serrated adenoma (TSA) remains the least understood of all the colorectal adenomas, although these lesions have been associated with a significant cancer risk, twice that of the conventional adenoma (CAD) and of the sessile serrated adenoma (SSA/P). This study was performed to investigate the proteomic profiles of the different colorectal adenomas to better understand the pathogenesis of TSA. We performed a global quantitative proteome analysis using the label‐free quantification (LFQ) method on 44 colorectal adenoma (12 TSAs, 15 CADs, and 17 SSA/Ps) and 17 normal colonic mucosa samples, archived as formalin‐fixed paraffin‐embedded blocks. Unsupervised consensus hierarchical clustering applied to the whole proteomic profile of the 44 colorectal adenomas identified four subtypes: C1 and C2 were well‐individualized clusters composed of all the CADs (15/15) and most of the SSA/Ps (13/17), respectively. This is consistent with the fact that CADs and SSA/Ps are homogeneous and distinct colorectal adenoma entities. In contrast, TSAs were subdivided into C3 and C4 clusters, consistent with the more heterogeneous entity of TSA at the morphologic and molecular levels. Comparison of the proteome expression profile between the adenoma subtypes and normal colonic mucosa further confirmed the heterogeneous nature of TSAs, which overlapped either on CADs or SSA/Ps, whereas CADs and SSAs formed homogeneous and distinct entities. Furthermore, we identified LEFTY1 a new potential marker for TSAs that may be relevant for the pathogenesis of TSA. LEFTY1 is an inhibitor of the Nodal/TGFβ pathway, which we found to be one of the most overexpressed proteins specifically in TSAs. This finding was confirmed by immunohistochemistry. Our study confirms that CADs and SSA/Ps form homogeneous and distinct colorectal adenoma entities, whereas TSAs are a heterogeneous entity and may arise from either SSA/Ps or from normal mucosa evolving through a process related to the CAD pathway. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-12-17
  • Interpretation of somatic POLE mutations in endometrial carcinoma
    J. Pathol. (IF 5.942) Pub Date : 2019-12-12
    Alicia León‐Castillo; Heidi Britton; Melissa K. McConechy; Jessica N. McAlpine; Remi Nout; Stefan Kommoss; Sara Y. Brucker; Joseph W. Carlson; Elisabeth Epstein; Tilman Rau; Tjalling Bosse; David N Church; C. Blake Gilks

    Pathogenic somatic missense mutations within the DNA polymerase epsilon (POLE) exonuclease domain define the important subtype of ultramutated tumours (“POLE‐ultramutated”) within the novel molecular classification of endometrial carcinoma (EC). However, clinical implementation of this classifier requires systematic evaluation of the pathogenicity of POLE mutations. To address this, we examined base changes, tumour mutational burden (TMB), DNA microsatellite instability (MSI) status, POLE variant frequency and the results from six in silico tools on 82 EC with whole‐exome sequencing from The Cancer Genome Atlas (TCGA). Of these, 41 had one of five known pathogenic POLE exonuclease domain mutations (EDM) and showed characteristic genomic alterations: C>A substitution >20%, T>G substitutions >4%, C>G substitutions < 0.6%, indels < 5%, TMB > 100mut/Mb. A scoring system to assess these alterations (POLE‐score) was developed; based on their scores 7/18 (39%) additional tumours with EDM were classified as POLE‐ultramutated EC, and the 6 POLE mutations present in these tumours were considered pathogenic. Only 1/23 (4%) tumours with non‐EDM showed these genomic alterations, indicating that a large majority of mutations outside the exonuclease domain are not pathogenic. The infrequent combination of MSI‐H with POLE EDM led us to investigate the clinical significance of this association. Tumours with pathogenic POLE EDM co‐existent with MSI‐H showed genomic alterations characteristic of POLE‐ultramutated EC. In a pooled analysis of 3,361 EC, 13 EC with DNA mismatch repair deficiency(MMRd)/MSI‐H and a pathogenic POLE EDM had a 5‐year recurrence‐free survival (RFS) of 92.3%, comparable to previously reported POLE‐ultramutated EC. Additionally, 14 cases with non‐pathogenic POLE EDM and MMRd/MSI‐H had 5‐year RFS of 76.2%, similar to MMRd/MSI‐H, POLE wild‐type EC, suggesting these should be categorised as MMRd, rather than POLE‐ultramutated EC for prognostication. This work provides guidance on classification of EC with POLE mutations, facilitating implementation of POLE testing in routine clinical care.

    更新日期:2019-12-13
  • p53 immunohistochemistry is an accurate surrogate for TP53 mutational analysis in endometrial carcinoma biopsies
    J. Pathol. (IF 5.942) Pub Date : 2019-12-12
    Naveena Singh; Anna M. Piskorz; Tjalling Bosse; Mercedes Jimenez‐Linan; Brian Rous; James D. Brenton; C Blake Gilks; Martin Köbel

    TP53 mutations are considered a surrogate biomarker of the serous‐like “copy number high” molecular subtype of endometrial carcinoma (EC). In ovarian carcinoma, p53 immunohistochemistry (IHC) accurately reflects mutational status with almost 100% specificity but its performance in EC has not been established. This study tested whether p53 IHC reliably predicts TP53 mutations identified by next generation sequencing (NGS) in EC biopsy samples for all EC and as part of a molecular classification algorithm after exclusion of cases harbouring mismatch repair defects (MMRd) or pathogenic DNA polymerase epsilon exonuclease domain mutations (POLEmut). A secondary aim assessed inter‐laboratory variability in p53 IHC.

    更新日期:2019-12-13
  • Clarin‐1 expression in adult mouse and human retina highlights a role of Müller glia in Usher syndrome
    J. Pathol. (IF 5.942) Pub Date : 2019-12-04
    Lei Xu, Susan N Bolch, Clayton P Santiago, Frank M Dyka, Omar Akil, Ekaterina S Lobanova, Yuchen Wang, Kirill A Martemyanov, William W Hauswirth, W Clay Smith, James T Handa, Seth Blackshaw, John D Ash, Astra Dinculescu

    Usher syndrome type 3 (USH3) is an autosomal recessively inherited disorder caused by mutations in the gene clarin‐1 (CLRN1), leading to combined progressive hearing loss and retinal degeneration. The cellular distribution of CLRN1 in the retina remains uncertain, either because its expression levels are low or because its epitopes are masked. Indeed, in the adult mouse retina, Clrn1 mRNA is developmentally downregulated, detectable only by RT‐PCR. In this study we used the highly sensitive RNAscope in situ hybridization assay and single‐cell RNA‐sequencing techniques to investigate the distribution of Clrn1 and CLRN1 in mouse and human retina, respectively. We found that Clrn1 transcripts in mouse tissue are localized to the inner retina during postnatal development and in adult stages. The pattern of Clrn1 mRNA cellular expression is similar in both mouse and human adult retina, with CLRN1 transcripts being localized in Müller glia, and not photoreceptors. We generated a novel knock‐in mouse with a hemagglutinin (HA) epitope‐tagged CLRN1 and showed that CLRN1 is expressed continuously at the protein level in the retina. Following enzymatic deglycosylation and immunoblotting analysis, we detected a single CLRN1‐specific protein band in homogenates of mouse and human retina, consistent in size with the main CLRN1 isoform. Taken together, our results implicate Müller glia in USH3 pathology, placing this cell type to the center of future mechanistic and therapeutic studies to prevent vision loss in this disease. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

    更新日期:2019-12-05
  • Recent advances in chronic obstructive pulmonary disease pathogenesis: from disease mechanisms to precision medicine
    J. Pathol. (IF 5.942) Pub Date : 2019-12-03
    Corry‐Anke Brandsma, Maarten Van den Berge, Tillie‐Louise Hackett, Guy Brusselle, Wim Timens

    Chronic obstructive pulmonary disease (COPD) is a devastating lung disease with a high personal and societal burden. Exposure to toxic particles and gases, including cigarette smoke, is the main risk factor for COPD. Together with smoking cessation, current treatment strategies of COPD aim to improve symptoms and prevent exacerbations, but there is no disease‐modifying treatment. The biggest drawback of today's COPD treatment regimen is the ‘one size fits all’ pharmacological intervention, mainly based on disease severity and symptoms and not the individual's disease pathology. To halt the worrying increase in the burden of COPD, disease management needs to be advanced with a focus on personalized treatment. The main pathological feature of COPD includes a chronic and abnormal inflammatory response within the lungs, which results in airway and alveolar changes in the lung as reflected by (small) airways disease and emphysema. Here we discuss recent developments related to the abnormal inflammatory response, ECM and age‐related changes, structural changes in the small airways and the role of sex‐related differences, which are all relevant to explain the individual differences in the disease pathology of COPD and improve disease endotyping. Furthermore, we will discuss the most recent developments of new treatment strategies using biologicals to target specific pathological features or disease endotypes of COPD. © 2019 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

    更新日期:2019-12-04
  • The transcription factor FOXM1 regulates the balance between proliferation and aberrant differentiation in head and neck squamous cell carcinoma
    J. Pathol. (IF 5.942) Pub Date : 2019-12-03
    Vincent Roh, Agnès Hiou‐Feige, Vinko Misetic, Jean‐Paul Rivals, Jana Sponarova, Muy‐Teck Teh, Silvia Ferreira Lopes, Zinnia Truan, Maxime Mermod, Yan Monnier, Jochen Hess, Genrich V Tolstonog, Christian Simon

    Sustained expression of FOXM1 is a hallmark of nearly all human cancers including squamous cell carcinomas of the head and neck (HNSCC). HNSCCs partially preserve the epithelial differentiation program, which recapitulates fetal and adult traits of the tissue of tumor origin but is deregulated by genetic alterations and tumor‐supporting pathways. Using shRNA‐mediated knockdown, we demonstrate a minimal impact of FOXM1 on proliferation and migration of HNSCC cell lines under standard cell culture conditions. However, FOXM1 knockdown in three‐dimensional (3D) culture and xenograft tumor models resulted in reduced proliferation, decreased invasion, and a more differentiated‐like phenotype, indicating a context‐dependent modulation of FOXM1 activity in HNSCC cells. By ectopic overexpression of FOXM1 in HNSCC cell lines, we demonstrate a reduced expression of cutaneous‐type keratin K1 and involucrin as a marker of squamous differentiation, supporting the role of FOXM1 in modulation of aberrant differentiation in HNSCC. Thus, our data provide a strong rationale for targeting FOXM1 in HNSCC. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-12-04
  • ALDH1A1‐related stemness in high‐grade serous ovarian cancer is a negative prognostic indicator but potentially targetable by EGFR/mTOR‐PI3K/aurora kinase inhibitors
    J. Pathol. (IF 5.942) Pub Date : 2019-12-03
    Katja Kaipio, Ping Chen, Pia Roering, Kaisa Huhtinen, Piia Mikkonen, Päivi Östling, Laura Lehtinen, Naziha Mansuri, Taina Korpela, Swapnil Potdar, Johanna Hynninen, Annika Auranen, Seija Grénman, Krister Wennerberg, Sampsa Hautaniemi, Olli Carpén

    Poor chemotherapy response remains a major treatment challenge for high‐grade serous ovarian cancer (HGSC). Cancer stem cells are the major contributors to relapse and treatment failure as they can survive conventional therapy. Our objectives were to characterise stemness features in primary patient‐derived cell lines, correlate stemness markers with clinical outcome and test the response of our cells to both conventional and exploratory drugs. Tissue and ascites samples, treatment‐naive and/or after neoadjuvant chemotherapy, were prospectively collected. Primary cancer cells, cultured under conditions favouring either adherent or spheroid growth, were tested for stemness markers; the same markers were analysed in tissue and correlated with chemotherapy response and survival. Drug sensitivity and resistance testing was performed with 306 oncology compounds. Spheroid growth condition HGSC cells showed increased stemness marker expression (including aldehyde dehydrogenase isoform I; ALDH1A1) as compared with adherent growth condition cells, and increased resistance to platinum and taxane. A set of eight stemness markers separated treatment‐naive tumours into two clusters and identified a distinct subgroup of HGSC with enriched stemness features. Expression of ALDH1A1, but not most other stemness markers, was increased after neoadjuvant chemotherapy and its expression in treatment‐naive tumours correlated with chemoresistance and reduced survival. In drug sensitivity and resistance testing, five compounds, including two PI3K‐mTOR inhibitors, demonstrated significant activity in both cell culture conditions. Thirteen compounds, including EGFR, PI3K‐mTOR and aurora kinase inhibitors, were more toxic to spheroid cells than adherent cells. Our results identify stemness markers in HGSC that are associated with a decreased response to conventional chemotherapy and reduced survival if expressed by treatment‐naive tumours. EGFR, mTOR‐PI3K and aurora kinase inhibitors are candidates for targeting this cell population. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-12-04
  • CD70 expression correlates with a worse prognosis in malignant pleural mesothelioma patients via immune evasion and enhanced invasiveness
    J. Pathol. (IF 5.942) Pub Date : 2019-12-03
    Shingo Inaguma, Jerzy Lasota, Piotr Czapiewski, Renata Langfort, Janusz Rys, Joanna Szpor, Piotr Waloszczyk, Krzysztof Okoń, Wojciech Biernat, David S Schrump, Raffit Hassan, Kenji Kasai, Markku Miettinen, Hiroshi Ikeda

    Diffuse malignant mesothelioma of the pleura (MPM) is a highly aggressive tumour that typically is associated with short survival. CD70 and CD27 belong to the tumour necrosis factor (TNF) and the TNF receptor (TNFR) superfamily, respectively. Under physiological conditions, the tightly regulated interaction between CD70 and CD27 plays a co‐stimulatory role in promoting T‐cell expansion and differentiation through the NFκB pathway. Aberrantly high CD70 expression has been documented in haematological and solid malignancies in association with immune evasion in malignant cells. In this study, 172 well‐characterised primary diffuse MPM tumours including epithelioid (n = 145), biphasic (n = 15), and sarcomatoid (n = 12) histotypes were evaluated immunohistochemically for CD70, CD27, CD3, CD4, CD8, CD56, PDCD1 (PD‐1), and FOXP3 expression. Twenty per cent (34/172) of the mesothelioma cells expressed CD70 on the cell membrane. Overall survival was significantly decreased in the cohort of patients with CD70‐expressing tumour cells (p < 0.01). Patients with MPM containing a higher number of CD3+ (p < 0.01), CD4+ (p < 0.01), CD8+ (p < 0.01), or FOXP3+ (p < 0.01) tumour‐infiltrating lymphoid cells (TILs) showed significantly worse clinical outcomes. As potential independent risk factors for MPM patients, multivariate Cox proportional hazards regression analysis revealed CD70 expression on mesothelioma cells [hazard ratio (HR) 2.25; p = 0.010], higher FOXP3+ TILs (HR 2.81; p = 0.004), and higher CD3+ TIL accumulation (HR 6.12; p < 0.001). In contrast, as a potential independent favourable factor, higher CD27+ TIL accumulation (HR 0.48; p = 0.037) was identified. In vitro experiments and an immunodeficient mouse model revealed that CD70 enhances the invasiveness of MPM cells through MET–ERK axis activation. Further analyses in syngeneic mouse models demonstrated possible roles for CD70 in immune evasion. Collectively, these findings suggest that the CD70–CD27 pathway enhances the malignant phenotypes of MPM and diminishes anti‐tumor immune response in patients with these neoplasms. These markers might be useful in MPM for prognostic evaluations as well as targeted therapeutics. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-12-03
  • Elucidating the roles of ASPM isoforms reveals a novel prognostic marker for pancreatic cancer
    J. Pathol. (IF 5.942) Pub Date : 2019-12-02
    Michael Timaner, Yuval Shaked

    Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers worldwide. Late diagnosis, desmoplastic tissue and intrinsic resistance to therapy are among the main reasons for its aggressive phenotype. In addition, it is now appreciated that cancer stem cells – a rare subpopulation of tumor cells highly resistant to therapy – are crucial players in PDAC initiation, progression and resistance to therapy. In a recent article in The Journal of Pathology, Hsu et al elucidated the specific roles of abnormal spindle‐like, microcephaly‐associated protein (ASPM) isoforms in PDAC. The authors reported that ASPM isoform I (ASPM‐iI) is mainly expressed in the cytoplasm of PDAC cells. Its expression is associated with the Wnt signaling pathway, which promotes stemness and maintains the cancer stem cell niche. Clinically, expression of ASPM‐iI correlates with poor survival in PDAC patients. Thus, this study revealed a novel prognostic marker as well as a potential therapeutic target for PDAC. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-12-03
  • BTK inhibitors synergise with 5‐FU to treat drug‐resistant TP53‐null colon cancers
    J. Pathol. (IF 5.942) Pub Date : 2019-12-02
    Marialuisa Lavitrano, Leonarda Ianzano, Sara Bonomo, Annamaria Cialdella, Maria Grazia Cerrito, Fabio Pisano, Carola Missaglia, Roberto Giovannoni, Gabriele Romano, Chelsea M McLean, Emile E Voest, Filomena D'Amato, Barbara Noli, Gian Luca Ferri, Marco Agostini, Salvatore Pucciarelli, Kristian Helin, Biagio E Leone, Vincenzo Canzonieri, Emanuela Grassilli

    Colorectal cancer (CRC) is the fourth cause of death from cancer worldwide mainly due to the high incidence of drug‐resistance. During a screen for new actionable targets in drug‐resistant tumours we recently identified p65BTK – a novel oncogenic isoform of Bruton's tyrosine kinase. Studying three different cohorts of patients here we show that p65BTK expression correlates with histotype and cancer progression. Using drug‐resistant TP53‐null colon cancer cells as a model we demonstrated that p65BTK silencing or chemical inhibition overcame the 5‐fluorouracil resistance of CRC cell lines and patient‐derived organoids and significantly reduced the growth of xenografted tumours. Mechanistically, we show that blocking p65BTK in drug‐resistant cells abolished a 5‐FU‐elicited TGFB1 protective response and triggered E2F‐dependent apoptosis. Taken together, our data demonstrated that targeting p65BTK restores the apoptotic response to chemotherapy of drug‐resistant CRCs and gives a proof‐of‐concept for suggesting the use of BTK inhibitors in combination with 5‐FU as a novel therapeutic approach in CRC patients. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-12-03
  • Fusobacterium nucleatum facilitates ulcerative colitis through activating IL‐17F signaling to NF‐κB via the upregulation of CARD3 expression
    J. Pathol. (IF 5.942) Pub Date : 2019-12-02
    Yongyu Chen, Yan Chen, Pan Cao, Wenhao Su, Na Zhan, Weiguo Dong

    Accumulating evidence links Fusobacterium nucleatum with ulcerative colitis (UC). The mechanism by which F. nucleatum promotes intestinal inflammation in UC remains poorly defined. Here, we first examined the abundance and impact of F. nucleatum on disease activity in UC tissues. Next, we isolated a strain of F. nucleatum from UC tissues and explored whether F. nucleatum aggravates the intestinal inflammatory response in vitro and in vivo. We also examined whether F. nucleatum infection involves the NF‐κB or IL‐17F signaling pathways. Our data showed that F. nucleatum was enriched in 51.78% of UC tissues and was correlated with the clinical course, clinical activity and refractory behavior of UC (p < 0.05). Furthermore, we demonstrated that F. nucleatum promoted intestinal epithelial damage and the expression of the inflammatory cytokines IL‐1β, Il‐6, IL‐17F and TNF‐α. Mechanistically, F. nucleatum targeted caspase activation and recruitment domain 3 (CARD3) through NOD2 to activate the IL‐17F/NF‐κB pathway in vivo and in vitro. Thus, F. nucleatum orchestrates a molecular network involving CARD3 and IL‐17F to control the UC process. Measuring and targeting F. nucleatum and its associated pathways will yield valuable insight into the prevention and treatment of UC. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-12-03
  • Whole‐genome sequencing of synchronous thyroid carcinomas identifies aberrant DNA repair in thyroid cancer dedifferentiation
    J. Pathol. (IF 5.942) Pub Date : 2019-11-29
    Johan O Paulsson, Samuel Backman, Na Wang, Adam Stenman, Joakim Crona, Jessada Thutkawkorapin, Mehran Ghaderi, Emma Tham, Peter Stålberg, Jan Zedenius, C Christofer Juhlin

    The genetics underlying thyroid cancer dedifferentiation is only partly understood and has not yet been characterised using comprehensive pan‐genomic analyses. We investigated a unique case with synchronous follicular thyroid carcinoma (FTC), poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid carcinoma (ATC), as well as regional lymph node metastases from the PDTC and ATC from a single patient using whole‐genome sequencing (WGS). The FTC displayed mutations in CALR, RB1, and MSH2, and the PDTC exhibited mutations in TP53, DROSHA, APC, TERT, and additional DNA repair genes – associated with an immense increase in sub‐clonal somatic mutations. All components displayed an overrepresentation of C>T transitions with associated microsatellite instability (MSI) in the PDTC and ATC, with borderline MSI in the FTC. Clonality analyses pinpointed a shared ancestral clone enriched for mutations in TP53‐associated regulation of DNA repair and identified important sub‐clones for each tumour component already present in the corresponding preceding lesion. This genomic characterisation of the natural progression of thyroid cancer reveals several novel genes of interest for future studies. Moreover, the findings support the theory of a stepwise dedifferentiation process and suggest that defects in DNA repair could play an important role in the clonal evolution of thyroid cancer. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-11-30
  • Oncogenic BRAF and KRAS mutations in endosalpingiosis
    J. Pathol. (IF 5.942) Pub Date : 2019-11-29
    Michael Herman Chui, Ie‐Ming Shih

    Endosalpingiosis, a microscopic lesion composed of ectopic Fallopian tube epithelium, frequently involves the peritoneum and lymph nodes in patients with ovarian serous borderline tumour or low‐grade serous carcinoma, but its pathogenic significance remains unclear. Using laser‐capture microdissection and droplet digital PCR, we investigated whether endosalpingiosis harbours the driver mutations in BRAF and KRAS that characterise ovarian low‐grade serous neoplasms. Somatic mutations were detected in 14 (33%) of 43 endosalpingiotic lesions analysed. Of 21 women with endosalpingiosis associated with a synchronous or metachronous ovarian low‐grade serous tumour, mutations were identified in endosalpingiotic lesions from 11 (52%) women, with most cases (10/11, 91%) demonstrating identical mutations in both tumour and endosalpingiosis. In contrast, of 13 cases of endosalpingiosis not associated with an ovarian tumour, only one harboured a KRAS mutation. The proliferative activity as assessed by Ki‐67 immunohistochemistry was lower in endosalpingiosis than in low‐grade serous tumours, and endosalpingiosis with either a BRAF or KRAS mutation had a significantly lower Ki‐67 index than those without. Ectopic expression of KRASG12V in Fallopian tube epithelial cells led to ERK phosphorylation, p21 induction, growth arrest and cellular senescence. In conclusion, we demonstrate that endosalpingiosis represents an interesting example of cancer driver mutations in deceptively normal‐appearing cells, which may be prone to neoplastic transformation upon bypass of endogenous oncosuppressive mechanisms. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-11-30
  • p38‐regulated FOXC1 stability is required for colorectal cancer metastasis
    J. Pathol. (IF 5.942) Pub Date : 2019-11-28
    Yi Zhang, Yan Liao, Chaoyi Chen, Wenjie Sun, Xiaohui Sun, Yuan Liu, Enping Xu, Maode Lai, Honghe Zhang

    Aberrant expression of forkhead box C1 (FOXC1) promotes tumor metastasis in multiple human malignant tumors. However, the upstream modulating mode and downstream molecular mechanism of FOXC1 in metastasis of colorectal cancer (CRC) remain unclear. Herein we describe a systematic analysis of FOXC1 expression and prognosis in CRC performed on our clinical data and public databases, which indicated that FOXC1 upregulation in CRC samples was significantly associated with poor prognosis. FOXC1 knockdown inhibited migration and invasion, whereas FOXC1 overexpression caused the opposite phenotype in vitro and in vivo. Furthermore, MMP10, SOX4 and SOX13 were verified as the target genes of FOXC1 for promoting CRC metastasis. MMP10 was demonstrated as the direct target and mediator of FOXC1. Interestingly, Ser241 and Ser272 of FOXC1 were identified as the key sites to interact with p38 and phosphorylation, which were critically required for maintaining the stability of FOXC1 protein. Moreover, FOXC1 was dephosphorylated by protein phosphatase 2A and phosphorylated by p38, which maintained FOXC1 protein stability through inhibiting ubiquitination. Expression of p38 was correlated with FOXC1 and MMP10 expression, indirectly indicating that FOXC1 was regulated by p38 MAPK. Therefore, FOXC1 is strongly suggested as a pro‐metastatic gene in CRC by transcriptionally activating MMP10, SOX4 and SOX13; p38 interacts with and phosphorylates the Ser241 and ser272 sites of FOXC1 to maintain its stability by inhibiting ubiquitination and degradation. In conclusion, the protein stability of FOXC1 mediated by p38 contributes to the metastatic effect in CRC. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-11-29
  • Prostate epithelial‐specific expression of activated PI3K drives stromal collagen production and accumulation
    J. Pathol. (IF 5.942) Pub Date : 2019-11-28
    Kyle A Wegner, Brett R Mueller, Christopher J Unterberger, Enrique J Avila, Hannah Ruetten, Anne E Turco, Steven R Oakes, Nicholas M Girardi, Richard B Halberg, Steven M Swanson, Paul C Marker, Chad M Vezina

    We genetically engineered expression of an activated form of P110 alpha, the catalytic subunit of PI3K, in mouse prostate epithelium to create a mouse model of direct PI3K activation (Pbsn‐cre4Prb;PI3KGOF/+). We hypothesized that direct activation would cause rapid neoplasia and cancer progression. Pbsn‐cre4Prb;PI3KGOF/+ mice developed widespread prostate intraepithelial hyperplasia, but stromal invasion was limited and overall progression was slower than anticipated. However, the model produced profound and progressive stromal remodeling prior to explicit epithelial neoplasia. Increased stromal cellularity and inflammatory infiltrate were evident as early as 4 months of age and progressively increased through 12 months of age, the terminal endpoint of this study. Prostatic collagen density and phosphorylated SMAD2‐positive prostatic stromal cells were expansive and accumulated with age, consistent with pro‐fibrotic TGF‐β pathway activation. Few reported mouse models accumulate prostate‐specific collagen to the degree observed in Pbsn‐cre4Prb;PI3KGOF/+. Our results indicate a signaling process beginning with prostatic epithelial PI3K and TGF‐β signaling that drives prostatic stromal hypertrophy and collagen accumulation. These mice afford a unique opportunity to explore molecular mechanisms of prostatic collagen accumulation that is relevant to cancer progression, metastasis, inflammation and urinary dysfunction. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-11-29
  • Prekallikrein inhibits innate immune signaling in the lung and impairs host defense during pneumosepsis in mice
    J. Pathol. (IF 5.942) Pub Date : 2019-11-25
    Chao Ding, Brendon P Scicluna, Ingrid Stroo, Jack Yang, Joris JTH Roelofs, Onno J de Boer, Alex F de Vos, Peter Nürnberg, Alexey S Revenko, Jeff Crosby, Cornelis van't Veer, Tom van der Poll

    Prekallikrein (PKK, also known as Fletcher factor and encoded by the gene KLKB1 in humans) is a component of the contact system. Activation of the contact system has been implicated in lethality in fulminant sepsis models. Pneumonia is the most frequent cause of sepsis. We sought to determine the role of PKK in host defense during pneumosepsis. To this end, mice were infected with the common human pathogen Klebsiella pneumoniae via the airways, causing an initially localized infection of the lungs with subsequent bacterial dissemination and sepsis. Mice were treated with a selective PKK‐directed antisense oligonucleotide (ASO) or a scrambled control ASO for 3 weeks prior to infection. Host response readouts were determined at 12 or 36 h post‐infection, including genome‐wide messenger RNA profiling of lungs, or mice were followed for survival. PKK ASO treatment inhibited constitutive hepatic Klkb1 mRNA expression by >80% and almost completely abolished plasma PKK activity. Klkb1 mRNA could not be detected in lungs. Pneumonia was associated with a progressive decline in PKK expression in mice treated with control ASO. PKK ASO administration was associated with a delayed mortality, reduced bacterial burdens, and diminished distant organ injury. While PKK depletion did not influence lung pathology or neutrophil recruitment, it was associated with an upregulation of multiple innate immune signaling pathways in the lungs already prior to infection. Activation of the contact system could not be detected, either during infection in vivo or at the surface of Klebsiella in vitro. These data suggest that circulating PKK confines pro‐inflammatory signaling in the lung by a mechanism that does not involve contact system activation, which in the case of respiratory tract infection may impede early protective innate immunity. © 2019 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

    更新日期:2019-11-27
  • Dysregulation of AMPA receptor subunit expression in sporadic ALS post‐mortem brain
    J. Pathol. (IF 5.942) Pub Date : 2019-11-23
    Jenna M Gregory, Matthew R Livesey, Karina McDade, Bhuvaneish T Selvaraj, Samantha K Barton, Siddharthan Chandran, Colin Smith

    Amyotrophic lateral sclerosis (ALS) is characterised by progressive motor neuron degeneration. Although there are over 40 genes associated with causal monogenetic mutations, the majority of ALS patients are not genetically determined. Causal ALS mutations are being increasingly mechanistically studied, though how these mechanisms converge and diverge between the multiple known familial causes of ALS (fALS) and sporadic forms of ALS (sALS) and furthermore between different neuron types, is poorly understood. One common pathway that is implicated in selective motor neuron death is enhanced α‐amino‐3‐hydroxyl‐5‐methyl‐4‐isoxazole‐propionate (AMPAR)‐mediated excitoxicity. Specifically, human in vitro and pathological evidence has linked the C9orf72 repeat expansion mutation to a relative increase in the Ca2+‐permeable AMPAR population due to AMPAR subunit dysregulation. Here, we provide the first comparative quantitative assessment of the expression profile of AMPAR subunit transcripts, using BaseScope, in post‐mortem lower motor neurons (spinal cord, anterior horn), upper motor neurons (motor cortex) and neurons of the pre‐frontal cortex in sALS and fALS due to mutations in SOD1 and C9orf72. Our data indicated that AMPAR dysregulation is prominent in lower motor neurons in all ALS cases. However, sALS and mutant C9orf72 cases exhibited GluA1 upregulation whereas mutant SOD1 cases displayed GluA2 down regulation. We also showed that sALS cases exhibited widespread AMPAR dysregulation in the motor and pre‐frontal cortex, though the exact identity of the AMPAR subunit being dysregulated was dependent on brain region. In contrast, AMPAR dysregulation in mutant SOD1 and C9orf72 cases was restricted to lower motor neurons only. Our data highlight the complex dysregulation of AMPAR subunit expression that reflects both converging and diverging mechanisms at play between different brain regions and between ALS cohorts. © 2019 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

    更新日期:2019-11-26
  • Inhibition of tissue‐nonspecific alkaline phosphatase protects against medial arterial calcification and improves survival probability in the CKD‐MBD mouse model
    J. Pathol. (IF 5.942) Pub Date : 2019-11-23
    Takashi Tani, Megumi Fujiwara, Hideo Orimo, Akira Shimizu, Sonoko Narisawa, Anthony B Pinkerton, José Luis Millán, Shuichi Tsuruoka

    Medial arterial calcification (MAC) is a major complication of chronic kidney disease (CKD) and an indicator of poor prognosis. Aortic overexpression of tissue‐nonspecific alkaline phosphatase (TNAP) accelerates MAC formation. The present study aimed to assess whether a TNAP inhibitor, SBI‐425, protects against MAC and improves survival probability in a CKD‐mineral and bone disorder (MBD) mouse model. CKD‐MBD mice were divided in three groups: vehicle, SBI‐10, and SBI‐30. They were fed a 0.2% adenine and 0.8% phosphorus diet from 14 to 20 weeks of age to induce CKD, followed by a high‐phosphorus (0.2% adenine and 1.8% phosphorus) diet for another 6 weeks. At 14–20 weeks of age, mice in the SBI‐10 and SBI‐30 groups were given 10 and 30 mg/kg SBI‐425 by gavage once a day, respectively, while vehicle‐group mice were given distilled water as vehicle. Control mice were fed a standard chow (0.8% phosphorus) between the ages of 8 and 20 weeks. Computed tomography imaging, histology, and aortic tissue calcium content revealed that, compared to vehicle animals, SBI‐425 nearly halted the formation of MAC. Mice in the control, SBI‐10 and SBI‐30 groups exhibited 100% survival, which was significantly better than vehicle‐treated mice (57.1%). Aortic mRNA expression of Alpl, encoding TNAP, as well as plasma and aortic tissue TNAP activity, were suppressed by SBI‐425 administration, whereas plasma pyrophosphate increased. We conclude that a TNAP inhibitor successfully protected the vasculature from MAC and improved survival rate in a mouse CKD‐MBD model, without causing any adverse effects on normal skeletal formation and residual renal function. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-11-26
  • Akt1 signalling supports acinar proliferation and limits acinar‐to‐ductal metaplasia formation upon induction of acute pancreatitis
    J. Pathol. (IF 5.942) Pub Date : 2019-11-22
    Rong Chen, Ermanno Malagola, Maren Dietrich, Richard Zuellig, Oliver Tschopp, Marta Bombardo, Enrica Saponara, Theresia Reding, Stephen Myers, Andrew P Hills, Rolf Graf, Sabrina Sonda

    Molecular signalling mediated by the phosphatidylinositol‐3‐kinase (PI3K)–Akt axis is a key regulator of cellular functions. Importantly, alteration of the PI3K–Akt signalling underlies the development of different human diseases, thus prompting the investigation of the pathway as a molecular target for pharmacologic intervention. In this regard, recent studies showed that small molecule inhibitors of PI3K, the upstream regulator of the pathway, reduced the development of inflammation during acute pancreatitis, a highly debilitating and potentially lethal disease. Here we investigated whether a specific reduction of Akt activity, by using either pharmacologic Akt inhibition, or genetic inactivation of the Akt1 isoform selectively in pancreatic acinar cells, is effective in ameliorating the onset and progression of the disease. We discovered that systemic reduction of Akt activity did not protect the pancreas from initial damage and only transiently delayed leukocyte recruitment. However, reduction of Akt activity decreased acinar proliferation and exacerbated acinar‐to‐ductal metaplasia (ADM) formation, two critical events in the progression of pancreatitis. These phenotypes were recapitulated upon conditional inactivation of Akt1 in acinar cells, which resulted in reduced expression of 4E‐BP1, a multifunctional protein of key importance in cell proliferation and metaplasia formation. Collectively, our results highlight the critical role played by Akt1 during the development of acute pancreatitis in the control of acinar cell proliferation and ADM formation. In addition, these results harbour important translational implications as they raise the concern that inhibitors of PI3K‐Akt signalling pathways may negatively affect the regeneration of the pancreas. Finally, this work provides the basis for further investigating the potential of Akt1 activators to boost pancreatic regeneration following inflammatory insults. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-11-26
  • Inflammatory macrophages switch to CCL17‐expressing phenotype and promote peritoneal fibrosis
    J. Pathol. (IF 5.942) Pub Date : 2019-11-22
    Yi‐Ting Chen, Hao Hsu, Chi‐Chun Lin, Szu‐Yu Pan, Shin‐Yun Liu, Ching‐Fang Wu, Pei‐Zhen Tsai, Chia‐Te Liao, Hui‐Teng Cheng, Wen‐Chih Chiang, Yung‐Ming Chen, Tzong‐Shinn Chu, Shuei‐Liong Lin

    Peritoneal fibrosis remains a problem in kidney failure patients treated with peritoneal dialysis. Severe peritoneal fibrosis with encapsulation or encapsulating peritoneal sclerosis is devastating and life‐threatening. Although submesothelial fibroblasts as the major precursor of scar‐producing myofibroblasts in animal models and M2 macrophage (Mϕ)‐derived chemokines in peritoneal effluents of patients before diagnosis of encapsulating peritoneal sclerosis have been identified, attenuation of peritoneal fibrosis is an unmet medical need partly because the mechanism for cross talk between Mϕs and fibroblasts remains unclear. We use a sodium hypochlorite‐induced mouse model akin to clinical encapsulated peritoneal sclerosis to study how the peritoneal Mϕs activate fibroblasts and fibrosis. Sodium hypochlorite induces the disappearance of CD11bhighF4/80high resident Mϕs but accumulation of CD11bintF4/80int inflammatory Mϕs (InfMϕs) through recruiting blood monocytes and activating local cell proliferation. InfMϕs switch to express chemokine (C‐C motif) ligand 17 (CCL17), CCL22, and arginase‐1 from day 2 after hypochlorite injury. More than 75% of InfMϕs undergo genetic recombination by Csf1r‐driven Cre recombinase, providing the possibility to reduce myofibroblasts and fibrosis by diphtheria toxin‐induced Mϕ ablation from day 2 after injury. Furthermore, administration of antibody against CCL17 can reduce Mϕs, myofibroblasts, fibrosis, and improve peritoneal function after injury. Mechanistically, CCL17 stimulates migration and collagen production of submesothelial fibroblasts in culture. By breeding mice that are induced to express red fluorescent protein in Mϕs and green fluorescence protein (GFP) in Col1a1‐expressing cells, we confirmed that Mϕs do not produce collagen in peritoneum before and after injury. However, small numbers of fibrocytes are found in fibrotic peritoneum of chimeric mice with bone marrow from Col1a1‐GFP reporter mice, but they do not contribute to myofibroblasts. These data demonstrate that InfMϕs switch to pro‐fibrotic phenotype and activate peritoneal fibroblasts through CCL17 after injury. CCL17 blockade in patients with peritoneal fibrosis may provide a novel therapy. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-11-26
  • Molecular mechanisms in chaperonopathies: clues to understanding the histopathological abnormalities and developing novel therapies
    J. Pathol. (IF 5.942) Pub Date : 2019-11-22
    Alberto JL Macario, Everly Conway de Macario

    Molecular chaperones, many of which are heat shock proteins (Hsps), are components of the chaperoning system and when defective can cause disease, the chaperonopathies. Chaperone‐gene variants cause genetic chaperonopathies, whereas in the acquired chaperonopathies the genes are normal, but their protein products are not, due to aberrant post‐transcriptional mechanisms, e.g. post‐translational modifications (PTMs). Since the chaperoning system is widespread in the body, chaperonopathies affect various tissues and organs, making these diseases of interest to a wide range of medical specialties. Genetic chaperonopathies are uncommon but the acquired ones are frequent, encompassing various types of cancer, and inflammatory and autoimmune disorders. The clinical picture of chaperonopathies is known. Much less is known on the impact that pathogenic mutations and PTMs have on the properties and functions of chaperone molecules. Elucidation of these molecular alterations is necessary for understanding the mechanisms underpinning the tissue and organ abnormalities occurring in patients. To illustrate this issue, we discuss structural–functional alterations caused by mutation in the chaperones CCT5 and HSPA9, and PTM effects on Hsp60. The data provide insights into what may happen when CCT5 and HSPA9 malfunction in patients, e.g. accumulation of cytotoxic protein aggregates with tissue destruction; or for Hsp60 with aberrant PTM, degradation and/or secretion of the chaperonin with mitochondrial damage. These and other possibilities are now open for investigation. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-11-26
  • Genetic or pharmacologic blockade of enhancer of zeste homolog 2 inhibits the progression of peritoneal fibrosis
    J. Pathol. (IF 5.942) Pub Date : 2019-11-14
    Yingfeng Shi, Min Tao, Yi Wang, Xiujuan Zang, Xiaoyan Ma, Andong Qiu, Shougang Zhuang, Na Liu

    Dysregulation of histone methyltransferase enhancer of zeste homolog 2 (EZH2) has been implicated in the pathogenesis of many cancers. However, the role of EZH2 in peritoneal fibrosis remains unknown. We investigated EZH2 expression in peritoneal dialysis (PD) patients and assessed its role in peritoneal fibrosis in cultured human peritoneal mesothelial cells (HPMCs) and murine models of peritoneal fibrosis induced by chlorhexidine gluconate (CG) or high glucose peritoneal dialysis fluid (PDF) by using 3‐deazaneplanocin A (3‐DZNeP), and EZH2 conditional knockout mice. An abundance of EZH2 was detected in the peritoneum of patients with PD associated peritonitis and the dialysis effluent of long‐term PD patients, which was positively correlated with expression of TGF‐β1, vascular endothelial growth factor, and IL‐6. EZH2 was found highly expressed in the peritoneum of mice following injury by CG or PDF. In both mouse models, treatment with 3‐DZNeP attenuated peritoneal fibrosis and inhibited activation of several profibrotic signaling pathways, including TGF‐β1/Smad3, Notch1, epidermal growth factor receptor and Src. EZH2 inhibition also inhibited STAT3 and nuclear factor‐κB phosphorylation, and reduced lymphocyte and macrophage infiltration and angiogenesis in the injured peritoneum. 3‐DZNeP effectively improved high glucose PDF‐associated peritoneal dysfunction by decreasing the dialysate‐to‐plasma ratio of blood urea nitrogen and increasing the ratio of dialysate glucose at 2 h after PDF injection to initial dialysate glucose. Moreover, delayed administration of 3‐DZNeP inhibited peritoneal fibrosis progression, reversed established peritoneal fibrosis and reduced expression of tissue inhibitor of metalloproteinase 2, and matrix metalloproteinase‐2 and ‐9. Finally, EZH2‐KO mice exhibited less peritoneal fibrosis than EZH2‐WT mice. In HPMCs, treatment with EZH2 siRNA or 3‐DZNeP suppressed TGF‐β1‐induced upregulation of α‐SMA and Collagen I and preserved E‐cadherin. These results indicate that EZH2 is a key epigenetic regulator that promotes peritoneal fibrosis. Targeting EZH2 may have the potential to prevent and treat peritoneal fibrosis. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-11-14
  • Lamin A/C deficiency in CD4+ T‐cells enhances regulatory T‐cells and prevents inflammatory bowel disease
    J. Pathol. (IF 5.942) Pub Date : 2019-10-30
    Raquel Toribio‐Fernández, Beatriz Herrero‐Fernandez, Virginia Zorita, Juan A López, Jesús Vázquez, Gabriel Criado, Jose L Pablos, Philippe Collas, Francisco Sánchez‐Madrid, Vicente Andrés, Jose M Gonzalez‐Granado

    The mechanisms by which lamin A/C in CD4+ T‐cells control intestinal homeostasis and can cause inflammatory bowel disease (IBD) are unknown. Here, we explore lamin A/C in a mouse model of IBD. Adoptive transfer to Rag1−/− mice of Lmna−/− CD4+ T‐cells, which have enhanced regulatory T‐cells (Treg) differentiation and function, induced less severe IBD than wild‐type T‐cells. Lamin A/C deficiency in CD4+ T‐cells enhanced transcription of the Treg master regulator FOXP3, thus promoting Treg differentiation, and reduced Th1 polarization, due to epigenetic changes in the Th1 master regulator T‐bet. In mesenteric lymph nodes, retinoic acid (RA) released by CD103+ dendritic cells downregulated lamin A/C in CD4+ T‐cells, enhancing Treg differentiation. However, non‐RA‐producing CD103− dendritic cells predominated in peripheral lymph nodes, facilitating lamin A/C expression in CD4+ T‐cells and therefore Th1 differentiation. Our findings establish lamin A/C as a key regulator of Th differentiation in physiological conditions and show it as a potential immune‐regulatory target in IBD. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-10-30
  • Repurposing an anti‐cancer agent for the treatment of hypertrophic heart disease
    J. Pathol. (IF 5.942) Pub Date : 2019-10-30
    Matthew Dukinfield, Eleni Maniati, Louise E Reynolds, Aisah Aubdool, Reshma S Baliga, Gabriela D'Amico, Oscar Maiques, Jun Wang, Kenneth C Bedi, Kenneth B Margulies, Victoria Sanz‐Moreno, Adrian Hobbs, Kairbaan Hodivala‐Dilke

    Coronary microvascular dysfunction combined with maladaptive cardiomyocyte morphology and energetics is a major contributor to heart failure advancement. Thus, dually enhancing cardiac angiogenesis and targeting cardiomyocyte function to slow, or reverse, the development of heart failure is a logical step towards improved therapy. We present evidence for the potential to repurpose a former anti‐cancer Arg‐Gly‐Asp (RGD)‐mimetic pentapeptide, cilengitide, here used at low doses. Cilengitide targets αvβ3 integrin and this protein is upregulated in human dilated and ischaemic cardiomyopathies. Treatment of mice after abdominal aortic constriction (AAC) surgery with low‐dose cilengitide (ldCil) enhances coronary angiogenesis and directly affects cardiomyocyte hypertrophy with an associated reduction in disease severity. At a molecular level, ldCil treatment has a direct effect on cardiac endothelial cell transcriptomic profiles, with a significant enhancement of pro‐angiogenic signalling pathways, corroborating the enhanced angiogenic phenotype after ldCil treatment. Moreover, ldCil treatment of Angiotensin II‐stimulated AngII‐stimulated cardiomyocytes significantly restores transcriptomic profiles similar to those found in normal human heart. The significance of this finding is enhanced by transcriptional similarities between AngII‐treated cardiomyocytes and failing human hearts. Taken together, our data provide evidence supporting a possible new strategy for improved heart failure treatment using low‐dose RGD‐mimetics with relevance to human disease. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

    更新日期:2019-10-30
  • Tumor mutational burden assessed by targeted NGS predicts clinical benefit from immune checkpoint inhibitors in non‐small cell lung cancer
    J. Pathol. (IF 5.942) Pub Date : 2019-10-24
    Ilaria Alborelli, Katharina Leonards, Sacha I Rothschild, Laura P Leuenberger, Spasenija Savic Prince, Kirsten D Mertz, Severin Poechtrager, Martin Buess, Alfred Zippelius, Heinz Läubli, Jasmin Haegele, Markus Tolnay, Lukas Bubendorf, Luca Quagliata, Philip Jermann

    In non‐small cell lung cancer (NSCLC), immune checkpoint inhibitors (ICIs) significantly improve overall survival (OS). Tumor mutational burden (TMB) has emerged as a predictive biomarker for patients treated with ICIs. Here, we evaluated the predictive power of TMB measured by the Oncomine™ Tumor Mutational Load targeted sequencing assay in 76 NSCLC patients treated with ICIs. TMB was assessed retrospectively in 76 NSCLC patients receiving ICI therapy. Clinical data (RECIST 1.1) were collected and patients were classified as having either durable clinical benefit (DCB) or no durable benefit (NDB). Additionally, genetic alterations and PD‐L1 expression were assessed and compared with TMB and response rate. TMB was significantly higher in patients with DCB than in patients with NDB (median TMB = 8.5 versus 6.0 mutations/Mb, Mann–Whitney p = 0.0244). 64% of patients with high TMB (cut‐off = third tertile, TMB ≥ 9) were responders (DCB) compared to 33% and 29% of patients with intermediate and low TMB, respectively (cut‐off = second and first tertile, TMB = 5–9 and TMB ≤ 4, respectively). TMB‐high patients showed significantly longer progression‐free survival (PFS) and OS (log‐rank test p = 0.0014 for PFS and 0.0197 for OS). While identifying different subgroups of patients, combining PD‐L1 expression and TMB increased the predictive power (from AUC 0.63 to AUC 0.65). Our results show that the TML panel is an effective tool to stratify patients for ICI treatment. A combination of biomarkers might maximize the predictive precision for patient stratification. Our study supports TMB evaluation through targeted NGS in NSCLC patient samples as a tool to predict response to ICI therapy. We offer recommendations for a reliable and cost‐effective assessment of TMB in a routine diagnostic setting. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

    更新日期:2019-10-24
  • The differential distributions of ASPM isoforms and their roles in Wnt signaling, cell cycle progression, and pancreatic cancer prognosis
    J. Pathol. (IF 5.942) Pub Date : 2019-10-23
    Chung‐Chi Hsu, Wen‐Ying Liao, Tze‐Sian Chan, Wei‐Yu Chen, Chung‐Ta Lee, Yan‐Shen Shan, Po‐Jui Huang, Ya‐Chin Hou, Chi‐Rong Li, Kelvin K Tsai

    Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and treatment‐resistant malignancy. The lack of pathway‐informed biomarkers hampers the development of rational diagnostics or therapies. Recently, the protein abnormal spindle‐like microcephaly‐associated (ASPM) was identified as a novel Wnt and stemness regulator in PDAC, while the pathogenic roles of its protein isoforms remain unclarified. We developed novel isoform‐specific antibodies and genetic knockdown (KD) of putative ASPM isoforms, whereby we uncovered that the levels of ASPM isoform 1 (iI) and ASPM‐iII are variably upregulated in PDAC cells. ASPM isoforms show remarkably different subcellular locations; specifically, ASPM‐iI is exclusively localized to the cortical cytoplasm of PDAC cells, while ASPM‐iII is predominantly expressed in cell nuclei. Mechanistically, ASPM‐iI co‐localizes with disheveled‐2 and active β‐catenin as well as the stemness marker aldehyde dehydrogenase‐1 (ALDH‐1), and its expression is indispensable for the Wnt activity, stemness, and the tumorigenicity of PDAC cells. By contrast, ASPM‐iII selectively regulates the expression level of cyclin E and cell cycle progression in PDAC cells. The expression of ASPM‐iI and ASPM‐iII displays considerable intratumoral heterogeneity in PDAC tissues and only that of ASPM‐iI was prognostically significant; it outperformed ALDH‐1 staining and clinico‐pathological variables in a multivariant analysis. Collectively, the distinct expression patterns and biological functions of ASPM isoforms may illuminate novel molecular mechanisms and prognosticators in PDAC and may pave the way for the development of therapies targeting this novel oncoprotein. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

    更新日期:2019-10-24
  • Next generation pathology: artificial intelligence enhances histopathology practice
    J. Pathol. (IF 5.942) Pub Date : 2019-10-23
    Balazs Acs, Johan Hartman

    Deep learning algorithms have shown benefits for pathology in the context of risk stratification of tumors. Although the results are promising, several steps have to be made to confirm clinical utility. In a recent issue of The Journal of Pathology, Colling et al present a perspective manuscript providing a roadmap to routine use of artificial intelligence in histopathology. In this commentary, we aimed to put these key points in the context of recent findings of AI and digital image analysis studies. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-10-24
  • Development of a predictive model for stromal content in prostate cancer samples to improve signature performance
    J. Pathol. (IF 5.942) Pub Date : 2019-10-16
    Nadia Boufaied, Mandeep Takhar, Claire Nash, Nicholas Erho, Tarek A Bismar, Elai Davicioni, Axel A Thomson

    Prostate cancer is heterogeneous in both cellular composition and patient outcome, and development of biomarker signatures to distinguish indolent from aggressive tumours is a high priority. Stroma plays an important role during prostate cancer progression and undergoes histological and transcriptional changes associated with disease. However, identification and validation of stromal markers is limited by a lack of datasets with defined stromal/tumour ratio. We have developed a prostate‐selective signature to estimate the stromal content in cancer samples of mixed cellular composition. We identified stromal‐specific markers from transcriptomic datasets of developmental prostate mesenchyme and prostate cancer stroma. These were experimentally validated in cell lines, datasets of known stromal content, and by immunohistochemistry in tissue samples to verify stromal‐specific expression. Linear models based upon six transcripts were able to infer the stromal content and estimate stromal composition in mixed tissues. The best model had a coefficient of determination R2 of 0.67. Application of our stromal content estimation model in various prostate cancer datasets led to improved performance of stromal predictive signatures for disease progression and metastasis. The stromal content of prostate tumours varies considerably; consequently, deconvolution of stromal proportion may yield better results than tumour cell deconvolution. We suggest that adjusting expression data for cell composition will improve stromal signature performance and lead to better prognosis and stratification of men with prostate cancer. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

    更新日期:2019-10-17
  • Making sense of Cbp/p300 loss of function mutations in skin tumorigenesis
    J. Pathol. (IF 5.942) Pub Date : 2019-10-09
    Sergio Anastasi, Stefano Alemà, Oreste Segatto

    CBP and p300 are highly homologous lysine acetyltransferases involved in cell cycle regulation, DNA synthesis and DNA repair. Loss of function mutations of CBP and p300 are found in about one‐third of cutaneous squamous cell carcinoma (cSCC) and often co‐occur, yet their role in cSCC pathogenesis is unclear. Writing in The Journal of Pathology, Ichise and colleagues modeled combined heterozygous loss of Cbp/p300 in mouse keratinocytes expressing a transgenic HrasS35 allele that allows selective coupling of Hras to the Erk pathway. Epidermal thickening caused by expression of HrasS35 was exacerbated by reduced dosage of Cbp/p300 and eventually resulted in development of skin papillomas. This phenotype was associated with reduced expression of Mig6, an Egfr feedback inhibitor, and attendant enhancement of Egfr signaling to the Ras‐Erk pathway. This model provides a mechanistic framework for understanding how Cbp/p300 loss of function mutations impact on skin tumorigenesis and suggests potential therapeutic options in CBP/p300 mutated human cSCC. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-10-10
  • Genomic characterisation of breast fibroepithelial lesions in an international cohort
    J. Pathol. (IF 5.942) Pub Date : 2019-10-08
    Nur Diyana Md Nasir, Cedric Chuan Young Ng, Vikneswari Rajasegaran, Suet Far Wong, Wei Liu, Gwendolene Xin Pei Ng, Jing Yi Lee, Peiyong Guan, Jing Quan Lim, Aye Aye Thike, Valerie Cui Yun Koh, Benjamin Nathanael Loke, Kenneth Tou En Chang, Mihir Ananta Gudi, Derrick Wen Quan Lian, Preetha Madhukumar, Benita Kiat Tee Tan, Veronique Kiak Mien Tan, Chow Yin Wong, Wei Sean Yong, Gay Hui Ho, Kong Wee Ong, , Patrick Tan, Bin Tean Teh, Puay Hoon Tan

    Fibroepithelial lesions (FELs) are a heterogeneous group of tumours comprising fibroadenomas (FAs) and phyllodes tumours (PTs). Here we used a 16‐gene panel that was previously discovered to be implicated in pathogenesis and progression, to characterise a large international cohort of FELs via targeted sequencing. The study comprised 303 (38%) FAs and 493 (62%) PTs which were contributed by the International Fibroepithelial Consortium. There were 659 (83%) Asian and 109 (14%) non‐Asian FELs, while the ethnicity of the rest was unknown. Genetic aberrations were significantly associated with increasing grade of PTs, and were detected more in PTs than FAs for MED12, TERT promoter, RARA, FLNA, SETD2, TP53, RB1, EGFR, and IGF1R. Most borderline and malignant PTs possessed ≥ 2 mutations, while there were more cases of FAs with ≤ 1 mutation compared to PTs. FELs with MED12 mutations had significantly higher rates of TERT promoter, RARA, SETD2, EGFR, ERBB4, MAP3K1, and IGF1R aberrations. However, FELs with wild‐type MED12 were more likely to express TP53 and PIK3CA mutations. There were no significant differences observed between the mutational profiles of recurrent FAs, FAs with a history of subsequent ipsilateral recurrence or contralateral occurrence, and FAs without a history of subsequent events. We identified recurrent mutations which were more frequent in PTs than FAs, with borderline and malignant PTs harbouring cancer driver gene and multiple mutations. This study affirms the role of a set of genes in FELs, including its potential utility in classification based on mutational profiles. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-10-10
  • IL‐10 from plasmacytoid dendritic cells promotes angiogenesis in the early stage of endometriosis
    J. Pathol. (IF 5.942) Pub Date : 2019-10-06
    Jau‐Ling Suen, Yu Chang, Yu‐Shiang Shiu, Chia‐Yi Hsu, Pooja Sharma, Chien‐Chih Chiu, Yi‐Ju Chen, Tzyh‐Chyuan Hour, Eing‐Mei Tsai

    An elevated level of IL‐10 has been considered a critical factor for the development of endometriosis; however, its detailed mechanism and causal relationship remain unclear. This study explored the cellular source and angiogenic activity of local IL‐10 during the early stage of endometriosis. Using a surgical murine model, we found that localised treatment with exogenous recombinant IL‐10 on the day of surgery significantly enhanced endometriotic lesion growth and angiogenesis, whereas blocking local IL‐10 activity using mAbs significantly suppressed those effects. Adoptive transfer of Il10+/+ plasmacytoid dendritic cells into mice significantly enhanced lesion development, whereas Il10−/− plasmacytoid dendritic cells significantly inhibited lesion development. Furthermore, in vitro angiogenesis analyses demonstrated that the IL‐10 and IL‐10 receptor pathway stimulated the migratory and tube formation ability of HUVECs as well as ectopic endometrial mesenchymal stem cells through, at least in part, a VEGF‐dependent pathway. We also found that recombinant IL‐10 directly stimulated angiogenesis, based on a Matrigel plug assay as well as a zebrafish model. Pathological results from human endometrioma tissues showed the increased infiltration of CD123+ plasmacytoid dendritic cells and higher percentages of cells that express the IL‐10 receptor and CD31 as compared with the corresponding normal counterparts. Taken together, these results show that IL‐10 secreted from local plasmacytoid dendritic cells promotes endometriosis development through pathological angiogenesis during the early disease stage. This study provides a scientific basis for a potential therapeutic strategy targeting the IL‐10—IL‐10 receptor pathway in the endometriotic milieu. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

    更新日期:2019-10-10
  • CDC42 promotes vascular calcification in chronic kidney disease
    J. Pathol. (IF 5.942) Pub Date : 2019-10-01
    Zehua Li, Ji Wu, Xiuli Zhang, Caiwen Ou, Xinglong Zhong, Yanting Chen, Lihe Lu, Hailin Liu, Yining Li, Xiaoyu Liu, Bo Wu, Yuxi Wang, Pingzhen Yang, Jianyun Yan, Minsheng Chen

    Vascular calcification is prevalent in patients with chronic kidney disease (CKD) and a major risk factor of cardiovascular disease. Vascular calcification is now recognised as a biological process similar to bone formation involving osteogenic differentiation of vascular smooth muscle cells (VSMCs). Cell division cycle 42 (CDC42), a Rac1 family member GTPase, is essential for cartilage development during endochondral bone formation. However, whether CDC42 affects osteogenic differentiation of VSMCs and vascular calcification remains unknown. In the present study, we observed a significant increase in the expression of CDC42 both in rat VSMCs and in calcified arteries during vascular calcification. Alizarin red staining and calcium content assay revealed that adenovirus‐mediated CDC42 overexpression led to an apparent VSMC calcification in the presence of calcifying medium, accompanied with up‐regulation of bone‐related molecules including RUNX2 and BMP2. By contrast, inhibition of CDC42 by ML141 significantly blocked calcification of VSMCs in vitro and aortic rings ex vivo. Moreover, ML141 markedly attenuated vascular calcification in rats with CKD. Furthermore, pharmacological inhibition of AKT signal was shown to block CDC42‐induced VSMC calcification. These findings demonstrate for the first time that CDC42 contributes to vascular calcification through a mechanism involving AKT signalling; this uncovered a new function of CDC42 in regulating vascular calcification. This may provide a potential therapeutic target for the treatment of vascular calcification in the context of CKD. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-10-01
  • Overactivity or blockade of transforming growth factor‐β each generate a specific ureter malformation
    J. Pathol. (IF 5.942) Pub Date : 2019-10-01
    Filipa M Lopes, Neil A Roberts, Leo AH Zeef, Natalie J Gardiner, Adrian S Woolf

    Transforming growth factor‐β (TGFβ) has been reported to be dysregulated in malformed ureters. There exists, however, little information on whether altered TGFβ levels actually perturb ureter development. We therefore hypothesised that TGFβ has functional effects on ureter morphogenesis. Tgfb1, Tgfb2 and Tgfb3 transcripts coding for TGFβ ligands, as well as Tgfbr1 and Tgfbr2 coding for TGFβ receptors, were detected by quantitative polymerase chain reaction in embryonic mouse ureters collected over a wide range of stages. As assessed by in situ hybridisation and immunohistochemistry, the two receptors were detected in embryonic urothelia. Next, TGFβ1 was added to serum‐free cultures of embryonic day 15 mouse ureters. These organs contain immature smooth muscle and urothelial layers and their in vivo potential to grow and acquire peristaltic function can be replicated in serum‐free organ culture. Such organs therefore constitute a suitable developmental stage with which to define roles of factors that affect ureter growth and functional differentiation. Exogenous TGFβ1 inhibited growth of the ureter tube and generated cocoon‐like dysmorphogenesis. RNA sequencing suggested that altered levels of transcripts encoding certain fibroblast growth factors (FGFs) followed exposure to TGFβ. In serum‐free organ culture exogenous FGF10 but not FGF18 abrogated certain dysmorphic effects mediated by exogenous TGFβ1. To assess whether an endogenous TGFβ axis functions in developing ureters, embryonic day 15 explants were exposed to TGFβ receptor chemical blockade; growth of the ureter was enhanced, and aberrant bud‐like structures arose from the urothelial tube. The muscle layer was attenuated around these buds, and peristalsis was compromised. To determine whether TGFβ effects were limited to one stage, explants of mouse embryonic day 13 ureters, more primitive organs, were exposed to exogenous TGFβ1, again generating cocoon‐like structures, and to TGFβ receptor blockade, again generating ectopic buds. As for the mouse studies, immunostaining of normal embryonic human ureters detected TGFβRI and TGFβRII in urothelia. Collectively, these observations reveal unsuspected regulatory roles for endogenous TGFβ in embryonic ureters, fine‐tuning morphogenesis and functional differentiation. Our results also support the hypothesis that the TGFβ up‐regulation reported in ureter malformations impacts on pathobiology. Further experiments are needed to unravel the intracellular signalling mechanisms involved in these dysmorphic responses. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

    更新日期:2019-10-01
  • Neuropilin‐2 contributes to tumor progression in preclinical models of small intestinal neuroendocrine tumors
    J. Pathol. (IF 5.942) Pub Date : 2019-09-03
    Julien Bollard, Céline Patte, Kristina Radkova, Patrick Massoma, Laurence Chardon, Julie Valantin, Nicolas Gadot, Isabelle Goddard, Cécile Vercherat, Valérie Hervieu, Géraldine Gouysse, Gilles Poncet, Jean‐Yves Scoazec, Thomas Walter, Colette Roche

    The identification of novel regulators of tumor progression is a key challenge to gain knowledge on the biology of small intestinal neuroendocrine tumors (SI‐NETs). We recently identified the loss of the axon guidance protein semaphorin 3F as a protumoral event in SI‐NETs. Interestingly the expression of its receptor neuropilin‐2 (NRP‐2) was still maintained. This study aimed at deciphering the potential role of NRP‐2 as a contributor to SI‐NET progression. The role of NRP‐2 in SI‐NET progression was addressed using an approach integrating human tissue and serum samples, cell lines and in vivo models. Data obtained from human SI‐NET tissues showed that membranous NRP‐2 expression is present in a majority of tumors, and is correlated with invasion, metastatic abilities, and neovascularization. In addition, NRP‐2 soluble isoform was found elevated in serum samples from metastatic patients. In preclinical mouse models of NET progression, NRP‐2 silencing led to a sustained antitumor effect, partly driven by the downregulation of VEGFR2. In contrast, its ectopic expression conferred a gain of aggressiveness, driven by the activation of various oncogenic signaling pathways. Lastly, NRP‐2 inhibition led to a decrease of tumor cell viability, and sensitized to therapeutic agents. Overall, our results point out NRP‐2 as a potential therapeutic target for SI‐NETs, and will foster the development of innovative strategies targeting this receptor. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-09-03
  • Computational pathology definitions, best practices, and recommendations for regulatory guidance: a white paper from the Digital Pathology Association
    J. Pathol. (IF 5.942) Pub Date : 2019-09-03
    Esther Abels, Liron Pantanowitz, Famke Aeffner, Mark D Zarella, Jeroen van der Laak, Marilyn M Bui, Venkata NP Vemuri, Anil V Parwani, Jeff Gibbs, Emmanuel Agosto‐Arroyo, Andrew H Beck, Cleopatra Kozlowski

    In this white paper, experts from the Digital Pathology Association (DPA) define terminology and concepts in the emerging field of computational pathology, with a focus on its application to histology images analyzed together with their associated patient data to extract information. This review offers a historical perspective and describes the potential clinical benefits from research and applications in this field, as well as significant obstacles to adoption. Best practices for implementing computational pathology workflows are presented. These include infrastructure considerations, acquisition of training data, quality assessments, as well as regulatory, ethical, and cyber‐security concerns. Recommendations are provided for regulators, vendors, and computational pathology practitioners in order to facilitate progress in the field. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

    更新日期:2019-09-03
  • Autoimmune response and its long‐term consequences after exon‐skipping therapy in a Duchenne muscular dystrophy mouse model†
    J. Pathol. (IF 5.942) Pub Date : 2019-08-31
    Joel Z Nordin, Yoshitsugu Aoki

    The progress of antisense‐based therapies using first generation Morpholino oligonucleotides for Duchenne muscular dystrophy (DMD) is expected to partially restore dystrophin expression and may prolong the lifespan of DMD patients. In a recent issue of The Journal of Pathology, a sophisticated study by Vila et al used a dystrophic mouse model of DMD to demonstrate that Morpholino‐induced exon skipping induced dystrophin expression in skeletal muscle and stimulated cell mediated and humoral responses to dystrophin. The study highlights the need to further investigate the autoimmune response against de novo synthesised truncated dystrophin protein and its long‐term consequences after exon‐skipping therapy for DMD. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-08-31
  • Mesenchymal transition and increased therapy resistance of glioblastoma cells is related to astrocyte reactivity
    J. Pathol. (IF 5.942) Pub Date : 2019-08-31
    Mia Niklasson, Tobias Bergström, Malin Jarvius, Anders Sundström, Frida Nyberg, Caroline Haglund, Rolf Larsson, Bengt Westermark, Bo Segerman, Anna Segerman

    Grade IV astrocytoma/glioblastoma multiforme (GBM) is essentially incurable, partly due to its heterogenous nature, demonstrated even within the glioma‐initiating cell (GIC) population. Increased therapy resistance of GICs is coupled to transition into a mesenchymal (MES) cell state. The GBM MES molecular signature displays a pronounced inflammatory character and its expression vary within and between tumors. Herein, we investigate how MES transition of GBM cells relates to inflammatory responses of normal astroglia. In response to CNS insults astrocytes enter a reactive cell state and participate in directing neuroinflammation and subsequent healing processes. We found that the MES signature show strong resemblance to gene programs induced in reactive astrocytes. Likewise, astrocyte reactivity gene signatures were enriched in therapy‐resistant MES‐like GIC clones. Variable expression of astrocyte reactivity related genes also largely defined intratumoral GBM cell heterogeneity at the single‐cell level and strongly correlated with our previously defined therapy‐resistance signature (based on linked molecular and functional characterization of GIC clones). In line with this, therapy‐resistant MES‐like GIC secreted immunoregulatory and tissue repair related proteins characteristic of astrocyte reactivity. Moreover, sensitive GIC clones could be made reactive through long‐term exposure to the proinflammatory cytokine interleukin 1 beta (IL1β). IL1β induced a slow MES transition, increased therapy resistance, and a shift in DNA methylation profile towards that of resistant clones, which confirmed a slow reprogramming process. In summary, GICs enter through MES transition a reactive‐astrocyte‐like cell state, connected to therapy resistance. Thus, from a biological point of view, MES GICs would preferably be called ‘reactive GICs’. The ability of GBM cells to mimic astroglial reactivity contextualizes the immunomodulatory and microenvironment reshaping abilities of GBM cells that generate a tumor‐promoting milieu. This insight will be important to guide the development of future sensitizing therapies targeting treatment‐resistant relapse‐driving cell populations as well as enhancing the efficiency of immunotherapies in GBM. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-08-31
  • Diabetes induces myeloid bias in bone marrow progenitors associated with enhanced wound macrophage accumulation and impaired healing
    J. Pathol. (IF 5.942) Pub Date : 2019-08-28
    Pijus K Barman, Norifumi Urao, Timothy J Koh

    Diabetes induces dysregulation throughout the spectrum of myeloid lineage cells from progenitors to terminally differentiated cells. Another complication of diabetes is persistent inflammation, including prolonged accumulation of macrophages, which contributes to impaired wound healing. However, it remains unclear whether diabetes disrupts the response of bone marrow progenitors to peripheral injury and whether such dysregulation leads to sustained inflammation and impaired healing. Here, we demonstrated that diabetic mice (db/db, referred to here as DB) exhibit myeloid lineage bias during homeostasis and following injury. In addition, cells in the LSK (Lin−Sca‐1+cKit+) population of DB mice are preprogrammed towards myeloid commitment at the transcriptional level, and cultured myeloid progenitors from DB mice produce more monocytes ex vivo than their non‐diabetic counterparts. We also show via bone marrow transfer between interleukin‐1 receptor 1 KO (Il1r1−/−) and DB mice that IL‐1R1 signaling is likely not involved in myeloid skewing in DB mice. Furthermore, in vitro experiments indicated that macrophage colony‐stimulating factor receptor signaling is not likely involved in enhanced myeloid transcription factor expression in LSK cells of DB mice. Our findings indicate that myeloid lineage commitment in bone marrow may contribute to increased macrophage numbers observed in diabetic skin wounds, and that strategies to regulate monopoiesis during homeostasis or post‐wounding may improve diabetic wound healing. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-08-28
  • Integrative genomic analysis of matched primary and metastatic pediatric osteosarcoma
    J. Pathol. (IF 5.942) Pub Date : 2019-08-28
    Gian Luca Negri, Bruno M Grande, Alberto Delaidelli, Amal El‐Naggar, Dawn Cochrane, Ching C Lau, Timothy J Triche, Richard A Moore, Steven JM Jones, Alexandre Montpetit, Marco A Marra, David Malkin, Ryan D Morin, Poul H Sorensen

    Despite being the most common childhood bone tumor, the genomic characterization of osteosarcoma remains incomplete. In particular, very few osteosarcoma metastases have been sequenced to date, critical to better understand mechanisms of progression and evolution in this tumor. We performed an integrated whole genome and exome sequencing analysis of paired primary and metastatic pediatric osteosarcoma specimens to identify recurrent genomic alterations. Sequencing of 13 osteosarcoma patients including 13 primary, 10 metastatic, and 3 locally recurring tumors revealed a highly heterogeneous mutational landscape, including cases of hypermutation and microsatellite instability positivity, but with virtually no recurrent alterations except for mutations involving the tumor suppressor genes RB1 and TP53. At the germline level, we detected alterations in multiple cancer related genes in the majority of the cohort, including those potentially disrupting DNA damage response pathways. Metastases retained only a minimal number of short variants from their corresponding primary tumors, while copy number alterations showed higher conservation. One recurrently amplified gene, KDR, was highly expressed in advanced cases and associated with poor prognosis. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-08-28
  • Autophagy contributes to BMP type 2 receptor degradation and development of pulmonary arterial hypertension
    J. Pathol. (IF 5.942) Pub Date : 2019-08-27
    Maria Catalina Gomez‐Puerto, Iris van Zuijen, Christopher JZ Huang, Robert Szulcek, Xiaoke Pan, Maarten AH van Dinther, Kondababu Kurakula, Catharina C Wiesmeijer, Marie‐Jose Goumans, Harm‐Jan Bogaard, Nicholas W Morrell, Amer Ahmed Rana, Peter ten Dijke

    Pulmonary arterial hypertension (PAH) is characterised by an increase in mean pulmonary arterial pressure which almost invariably leads to right heart failure and premature death. More than 70% of familial PAH and 20% of idiopathic PAH patients carry heterozygous mutations in the bone morphogenetic protein (BMP) type 2 receptor (BMPR2). However, the incomplete penetrance of BMPR2 mutations suggests that other genetic and environmental factors contribute to the disease. In the current study, we investigate the contribution of autophagy in the degradation of BMPR2 in pulmonary vascular cells. We demonstrate that endogenous BMPR2 is degraded through the lysosome in primary human pulmonary artery endothelial (PAECs) and smooth muscle cells (PASMCs): two cell types that play a key role in the pathology of the disease. By means of an elegant HaloTag system, we show that a block in lysosomal degradation leads to increased levels of BMPR2 at the plasma membrane. In addition, pharmacological or genetic manipulations of autophagy allow us to conclude that autophagy activation contributes to BMPR2 degradation. It has to be further investigated whether the role of autophagy in the degradation of BMPR2 is direct or through the modulation of the endocytic pathway. Interestingly, using an iPSC‐derived endothelial cell model, our findings indicate that BMPR2 heterozygosity alone is sufficient to cause an increased autophagic flux. Besides BMPR2 heterozygosity, pro‐inflammatory cytokines also contribute to an augmented autophagy in lung vascular cells. Furthermore, we demonstrate an increase in microtubule‐associated protein 1 light chain 3 beta (MAP1LC3B) levels in lung sections from PAH induced in rats. Accordingly, pulmonary microvascular endothelial cells (MVECs) from end‐stage idiopathic PAH patients present an elevated autophagic flux. Our findings support a model in which an increased autophagic flux in PAH patients contributes to a greater decrease in BMPR2 levels. Altogether, this study sheds light on the basic mechanisms of BMPR2 degradation and highlights a crucial role for autophagy in PAH. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

    更新日期:2019-08-27
  • Intratumour heterogeneity of p53 expression; causes and consequences
    J. Pathol. (IF 5.942) Pub Date : 2019-08-27
    Yuezhen Xue, Boris San Luis, David P Lane

    Genomic alterations in different types of cancer have been identified by comprehensive sequencing methodologies, revealing TP53 as the most frequently mutated gene across the majority of human cancer types. Cytotoxic treatments are still major cancer therapy strategies but cancer recurrence due to therapy resistance is a major challenge. Resistant cell populations may be associated with TP53 mutant clones exhibiting abnormal p53 expression patterns in tumours. Given data that levels of mutant p53 influence cancer cell growth and survival, understanding the mechanisms underlying intratumour heterogeneity of p53 can be exploited to design strategies that improve patient survival. The patterns of p53 protein examined by immunohistochemistry of both premalignant and malignant tissues are complex, ranging from intense staining of all tumour cell nuclei to complete absence of staining and with many intermediate phenotypes. Animal models that express only mutant proteins and adoption of international standards for terminology have brought greater clarity to understanding the causes of variation and are at the same time demonstrating the utility of p53 in oncology. In addition to p53 mutation, MDM2 and chaperone activities, gene copy number and TP53 mRNA levels linked to proliferative activity and differentiation are all now established as causes of variation in p53 staining, with clinical implications. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-08-27
  • A miR‐194/PTBP1/CCND3 axis regulates tumor growth in human hepatocellular carcinoma
    J. Pathol. (IF 5.942) Pub Date : 2019-08-27
    Hoin Kang, Sungeun Heo, Jung Jae Shin, Eunbyul Ji, Hyosun Tak, Sojin Ahn, Kyung Jin Lee, Eun Kyung Lee, Wook Kim

    Polypyrimidine tract‐binding protein 1 (PTBP1) is one of the most investigated multifunctional RNA‐binding proteins (RBP), controlling almost all steps of mRNA metabolism and processing. It has been reported that PTBP1 is overexpressed in many different types of cancer and this high expression is associated with increased proliferation and poor prognoses. However, there are no reports on a putative role for PTBP1 in the molecular abnormalities and pathogenesis of hepatocellular carcinoma (HCC). Here, we identified PTBP1 as a positive regulator of human HCC growth. The expression of PTBP1 was increased in human HCC cells and tissues compared to the corresponding controls, and this high expression was positively correlated with increased tumor size and a reduced survival rate. Mechanistically, PTBP1 enhanced cyclin D3 (CCND3) translation by interacting with the 5′‐untranslated region (5′‐UTR) of CCND3 mRNA, consequently facilitating cell cycle progression and tumor growth. Furthermore, we found that miR‐194 inhibits PTBP1 expression by binding to the 3′‐UTR of PTBP1 mRNA, resulting in reduced CCND3 levels and HCC cell growth; moreover, the levels of PTBP1 were negatively correlated with miR‐194 levels in HCC. Taken together, these findings identify PTBP1 as a pivotal enhancer of HCC growth; the miR‐194/PTBP1/CCND3 axis seemingly has a crucial role in the development and progression of HCC and targeting the axis could be a novel therapeutic strategy against human HCC. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-08-27
  • Undifferentiated pleomorphic sarcomas with PRDM10 fusions have a distinct gene expression profile
    J. Pathol. (IF 5.942) Pub Date : 2019-08-27
    Jakob Hofvander, Florian Puls, Nischalan Pillay, Christopher D Steele, Adrienne M Flanagan, Linda Magnusson, Jenny Nilsson, Fredrik Mertens

    Undifferentiated pleomorphic sarcoma (UPS) is a highly aggressive soft tissue tumor. A subset of UPS is characterized by a CITED2–PRDM10 or a MED12–PRDM10 gene fusion. Preliminary data suggest that these so‐called PRDM10‐rearranged tumors (PRT) are clinically more indolent than classical high‐grade UPS, and hence important to recognize. Here, we assessed the spectrum of accompanying mutations and the gene expression profile in PRT using genomic arrays and sequencing of the genome (WGS) and transcriptome (RNA‐seq). The fusion protein's function was further investigated by conditional expression of the CITED2–PRDM10 fusion in a fibroblast cell line, followed by RNA‐seq and an assay for transposase‐accessible chromatin (ATAC‐seq). The CADM3 gene was found to be differentially up‐regulated in PRT and cell lines and was also evaluated for expression at the protein level using immunohistochemistry (IHC). The genomic analyses identified few and nonrecurrent mutations in addition to the structural variants giving rise to the gene fusions, strongly indicating that the PRDM10‐fusions represent the critical driver mutations. RNA‐seq of tumors showed a distinct gene expression profile, separating PRT from high‐grade UPS and other soft tissue tumors. CADM3 was among the genes that was consistently and highly expressed in both PRT and fibroblasts expressing CITED2‐PRDM10, suggesting that it is a direct target of the PRDM10 transcription factor. This conclusion is in line with sequencing data from ATAC‐seq, showing enrichment of PRDM10 binding sites, suggesting that the amino‐terminal fusion partner contributes by making the DNA more accessible to PRDM10 binding. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

    更新日期:2019-08-27
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