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  • Multiple roles and context-specific mechanisms underlying YAP and TAZ-mediated resistance to anti-cancer therapy
    BBA Rev. Cancer (IF 6.887) Pub Date : 2020-01-10
    Francesca Reggiani; Giulia Gobbi; Alessia Ciarrocchi; Davide Carlo Ambrosetti; Valentina Sancisi

    Understanding the molecular mechanisms driving resistance to anti-cancer drugs is both a crucial step to define markers of response to therapy and a clinical need in many cancer settings. YAP and TAZ transcriptional cofactors behave as oncogenes in different cancer types. Deregulation of YAP/TAZ expression or alterations in components of the multiple signaling pathways converging on these factors are important mechanisms of resistance to chemotherapy, target therapy and hormone therapy. Moreover, response to immunotherapy may also be affected by YAP/TAZ activities in both tumor and microenvironment cells. For these reasons, various compounds inhibiting YAP/TAZ function by different direct and indirect mechanisms have been proposed as a mean to counter-act drug resistance in cancer. A particularly promising approach may be to simultaneously target both YAP/TAZ expression and their transcriptional activity through BET inhibitors.

    更新日期:2020-01-11
  • Communication in tiny packages: Exosomes as means of tumor-stroma communication
    BBA Rev. Cancer (IF 6.887) Pub Date : 2020-01-08
    Juliane Daßler-Plenker; Victoria Küttner; Mikala Egeblad

    Tumor-derived exosomes are nano-sized vesicles acting as multi-signal devices influencing tumor growth at local and distant sites. Exosomes are derived from the endolysosomal compartment and can shuttle diverse biomolecules like nucleic acids (microRNAs, DNA fragments), lipids, proteins and even pharmacological compounds from a donor cell to recipient cells. The transfer of cargo to recipient cells enables tumor-derived exosomes to influence diverse cellular functions like proliferation, cell survival and migration in recipient cells highlighting tumor-derived exosomes as important players in the communication within the tumor microenvironment and at distant sites. In this review, we will discuss mechanisms associated with exosome biogenesis and cargo sorting. In addition, we highlight the communication of tumor-derived exosomes in the tumor microenvironment during different phases of tumor development with a main focus on angiogenesis, immune escape mechanisms, drug resistance, and metastasis.

    更新日期:2020-01-09
  • BRCA1/P53: Two strengths in cancer chemoprevention
    BBA Rev. Cancer (IF 6.887) Pub Date : 2020-01-07
    Liliana Raimundo; Helena Ramos; Joana B. Loureiro; Juliana Calheiros; Lucília Saraiva

    Increasing emphasis has been given to prevention as a feasible approach to reduce the cancer burden. However, for its clinical success, further advances are required to identify effective chemopreventive agents. This review affords a critical and up-to-date discussion of issues related to cancer prevention, including an in-depth knowledge on BRCA1 and p53 tumor suppressor proteins as key molecular players. Indeed, it compiles the most recent advances on the topic, highlighting the unique potential of BRCA1 and p53 germline mutations as molecular biomarkers for risk assessment and targets for chemoprevention. Relevant evidences are herein provided supporting the effectiveness of distinct pharmacological agents in cancer prevention, by targeting BRCA1 and p53. Moreover, the rationale for using germline mutant BRCA1- or p53-related cancer syndromes as model systems to investigate effective chemopreventive agents is also addressed. Altogether, this work provides an innovative conception about the dependence on p53 and BRCA1 co-inactivation in tumor formation and development, emphasizing the relationship between these two proteins as an encouraging direction for future personalized pharmacological interventions in cancer prevention.

    更新日期:2020-01-07
  • The emerging role of paraptosis in tumor cell biology: Perspectives for cancer prevention and therapy with natural compounds
    BBA Rev. Cancer (IF 6.887) Pub Date : 2020-01-03
    Fabrizio Fontana; Michela Raimondi; Monica Marzagalli; Alessandro Di Domizio; Patrizia Limonta
    更新日期:2020-01-04
  • RLIP controls receptor-ligand signaling by regulating clathrin-dependent endocytosis
    BBA Rev. Cancer (IF 6.887) Pub Date : 2020-01-02
    Sharad S. Singhal; Ravi Salgia; Nisan Verma; David Horne; Sanjay Awasthi

    RLIP (Ral-interacting protein) is a multifunctional protein that couples ATP hydrolysis with the movement of substances. Its primary function appears to be in the plasma membrane, where it catalyzes the ATP-dependent efflux of glutathione-conjugates (GS-Es), as well as un-metabolized drugs and toxins. In the plasma membrane, its interaction with the clathrin adaptor protein AP2 localizes it to endocytic vesicle, where its GS-E-stimulated ATPase and transport activity are required for clathrin-dependent endocytosis (CDE). CDE is an essential mechanism for internalizing ligand-receptor complexes that signal proliferation (EGF, insulin, IGF1), apoptosis (TNFα, TRAIL, Fas-L), and differentiation and morphogenesis (TGFβ, WNT, Notch, SHH). Aberrant functioning of these pathways appears crucial for most cancer cells to evade apoptosis, invade surrounding tissues, and metastasize. Internalization of receptor-ligand complexes by CDE begins a sequence of events that can terminate, initiate, or modulate downstream signaling; the consequences of signaling through these downstream pathways may be inherently different in cancer and normal cells, a view supported by numerous basic and clinical observations. In this review, we will discuss the GS-E transport activity of RLIP, which determines the rate of ligand endocytosis, and how the inhibition and/or depletion of RLIP globally disrupts in ligand-receptor signaling.

    更新日期:2020-01-02
  • The conflicting role of E2F1 in prostate cancer: A matter of cell context or interpretational flexibility?
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-12-21
    Jung Nyeo Chun; Minsoo Cho; Soonbum Park; Insuk So; Ju-Hong Jeon

    The transcription factor E2F1 plays a crucial role in mediating multiple cancer hallmark capabilities that regulate cell cycle, survival, apoptosis, metabolism, and metastasis. Aberrant activation of E2F1 is closely associated with a poor clinical outcome in various human cancers. However, E2F1 has conflictingly been reported to exert tumor suppressive activity, raising a question as to the nature of its substantive role in the control of cell fate. In this review, we summarize deregulated E2F1 activity and its role in prostate cancer. We highlight the recent advances in understanding the molecular mechanism by which E2F1 regulates the development and progression of prostate cancer, providing insight into how cell context or data interpretation shapes the role of E2F1 in prostate cancer. This review will aid in translating biomedical knowledge into therapeutic strategies for prostate cancer.

    更新日期:2019-12-21
  • The role of AhR in transcriptional regulation of immune cell development and function
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-12-06
    Prashant Trikha, Dean A. Lee

    The aryl hydrocarbon receptor (AhR) is a ligand-activated transcriptional factor (TF) that is a member of the Per-Arnt-Sim family of proteins. AhR regulates diverse processes, including malignant transformation, hematopoietic cell development, and fate determination of immune cell lineages. Moreover, AhR forms a crucial link between innate and adaptive arms of the immune system. Malignant cells frequently evolve multiple mechanisms for suppressing tumor-specific responses, including the induction of suppressive pathways involving AhR and its metabolic byproducts in the tumor microenvironment that promote immune evasion and tumor progression. Thus, interest is high in further defining the role of AhR in carcinogenesis and immune development and regulation, particularly regarding the therapeutic interventions that unleash immune responses to cancer cells. Here, we provide an overview of the role of AhR in the regulation of innate and adaptive immune response and discuss the implications of targeting this pathway to augment the immune response in cancer patients.

    更新日期:2019-12-07
  • Mechanism of colorectal carcinogenesis triggered by heme iron from red meat
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-11-26
    Nina Seiwert, Daniel Heylmann, Solveig Hasselwander, Jörg Fahrer

    Colorectal cancer (CRC) is one of the major tumor entities worldwide, with an increasing incidence in younger people CRC formation is causally linked to various genetic, life-style and dietary risk factors. Among the ladder, the consumption of red meat has emerged as important risk factor contributing to CRC. A large body of evidence shows that heme iron is the critical component of red meat, which promotes colorectal carcinogenesis. In this review, we first describe the uptake and cellular fate of both heme and inorganic iron in intestinal epithelial cells. Next, an overview on the DNA damaging properties of heme iron is provided, highlighting the DNA adducts relevant for CRC etiology. Moreover, heme triggered mechanisms leading to colonic hyperproliferation are presented, which are intimately linked to changes in the intestinal microbiota induced by heme. A special focus was set on the impact of heme iron on innate and adaptive immune cells, which could be relevant in the context of CRC. Finally, we recapitulate in vivo studies providing evidence for the tumor-promoting potential of dietary heme iron. Altogether, heme iron affects numerous key pathways involved in the pathogenesis of CRC.

    更新日期:2019-11-27
  • 更新日期:2019-11-22
  • Targeting citrate as a novel therapeutic strategy in cancer treatment
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-11-18
    Lan Huang, Cindy Wang, Huaxi Xu, Guangyong Peng

    An important feature shared by many cancer cells is drastically altered metabolism that is critical for rapid growth and proliferation. The distinctly reprogrammed metabolism in cancer cells makes it possible to manipulate the levels of metabolites for cancer treatment. Citrate is a key metabolite that bridges many important metabolic pathways. Recent studies indicate that manipulating the level of citrate can impact the behaviors of both cancer and immune cells, resulting in induction of cancer cell apoptosis, boosting immune responses, and enhanced cancer immunotherapy. In this review, we discuss the recent developments in this emerging area of targeting citrate in cancer treatment. Specifically, we summarize the molecular basis of altered citrate metabolism in both tumors and immune cells, explore the seemingly conflicted growth promoting and growth inhibiting roles of citrate in various tumors, discuss the use of citrate in the clinic as a novel biomarker for cancer progression and outcomes, and highlight the new development of combining citrate with other therapeutic strategies in cancer therapy. An improved understanding of complex roles of citrate in the suppressive tumor microenvironment should open new avenues for cancer therapy.

    更新日期:2019-11-18
  • The intricate relationship between diabetes, obesity and pancreatic cancer
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-11-09
    Silvano Paternoster, Marco Falasca

    Pancreatic cancer is one of the leading determinants of global cancer mortality, and its incidence is predicted to increase, to become in 2030 the second most common cause of cancer-related death. Obesity and diabetes are recognized risk factors for the development of pancreatic cancer. In the last few decades an epidemic of diabetes and obesity has been spreading worldwide, forewarning an increase in incidence of pancreatic cancer. This review considers the most recent literature, covering the multiple molecular axis linking these three pathologies, aiming to draw a more comprehensive view of pancreatic cancer for a better theragnostic stratification of the population.

    更新日期:2019-11-11
  • Venous thromboembolism GWAS reported genetic makeup and the hallmarks of cancer: Linkage to ovarian tumour behaviour
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-11-02
    Valéria Tavares, Ricardo Pinto, Joana Assis, Deolinda Pereira, Rui Medeiros

    Venous thromboembolism (VTE) is a common cardiovascular disease thought to be the outcome of an intricate interplay between acquired and inherited factors that act together to modify disease risk. Over the years, several single-nucleotide polymorphisms (SNPs) in candidate genes have been associated with disease risk, including F5 rs6025, F2 rs1799963, FGG rs2066865, ABO genetic variants, among others less common. More recently, genome-wide association studies (GWAS) have contributed to the identification of novel VTE-associated SNPs, some of them located in novel genes with no clear role in the haemostatic system, such as SLC44A2 rs2288904 and TSPAN15 rs78707713. Given the existence of a tight relationship between VTE and cancer, with both pathologies sharing biological pathways that allow one to promote the other, these SNPs constitute potential prognostic and predictive biomarkers currently needed for better management of cancer patients. Among solid tumours, ovarian cancer (OC) is one of the most frequently associated with VTE. Indeed, haemostatic components might have a significant impact in OC progression, and therefore, the clinical and biological implications of VTE-associated SNPs should be assessed in patients with this neoplasia.

    更新日期:2019-11-04
  • Lipoic acid a multi-level molecular inhibitor of tumorigenesis
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-11-01
    D. Farhat, H. Lincet

    We discuss how lipoic acid (LA), a natural antioxidant, induces apoptosis and inhibits proliferation, EMT, metastasis and stemness of cancer cells. Furthermore, owing to its ability to reduce chemotherapy-induced side effects and chemoresistance, LA appears to be a promising compound for cancer treatment.

    更新日期:2019-11-01
  • Challenges in liver cancer and possible treatment approaches
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-11-01
    David Anwanwan, Santosh Kumar Singh, Shriti Singh, Varma Saikam, Rajesh Singh

    Globally, liver cancer is the most frequent fatal malignancy; in the United States, it ranks fifth. Patients are often diagnosed with liver cancer in advanced stages, contributing to its poor prognosis. Of all liver cancer cases, >90% are hepatocellular carcinomas (HCCs) for which chemotherapy and immunotherapy are the best options for therapy. For liver cancer patients, new treatment options are necessary. Use of natural compounds and/or nanotechnology may provide patients with better outcomes with lower systemic toxicity and fewer side effects. Improved treatments can lead to better prognoses. Finally, in this review, we present some of the problems and current treatment options contributing to the poor outcomes for patients with liver cancer.

    更新日期:2019-11-01
  • Harnessing the therapeutic potential of anticancer drugs through amorphous solid dispersions
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-10-31
    Urvi H. Gala, Dave A. Miller, Robert O. Williams

    The treatment of cancer is still a major challenge. But tremendous progress in anticancer drug discovery and development has occurred in the last few decades. However, this progress has resulted in few effective oncology products due to challenges associated with anticancer drug delivery. Oral administration is the most preferred route for anticancer drug delivery, but the majority of anticancer drugs currently in product pipelines and the majority of those that have been commercially approved have inherently poor water solubility, and this cannot be mitigated without compromising their potency and stability. The poor water solubility of anticancer drugs, in conjunction with other factors, leads to suboptimal pharmacokinetic performance. Thus, these drugs have limited efficacy and safety when administered orally. The amorphous solid dispersion (ASD) is a promising formulation technology that primarily enhances the aqueous solubility of poorly water-soluble drugs. In this review, we discuss the challenges associated with the oral administration of anticancer drugs and the use of ASD technology in alleviating these challenges. We emphasize the ability of ASDs to improve not only the pharmacokinetics of poorly water-soluble anticancer drugs, but also their efficacy and safety. The goal of this paper is to rationalize the application of ASD technology in the formulation of anticancer drugs, thereby creating superior oncology products that lead to improved therapeutic outcomes.

    更新日期:2019-11-01
  • Elevating pancreatic cystic lesion stratification: Current and future pancreatic cancer biomarker(s)
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-10-30
    Joseph Carmicheal, Asish Patel, Vipin Dalal, Pranita Atri, Amaninder S. Dhaliwal, Uwe A. Wittel, Mokenge P. Malafa, Geoffrey Talmon, Benjamin J. Swanson, Shailender Singh, Maneesh Jain, Sukhwinder Kaur, Surinder K. Batra
    更新日期:2019-11-01
  • Nervous system and gastric cancer
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-10-21
    Ke Wang, Xin-hui Zhao, Jun Liu, Rui Zhang, Ji-peng Li

    The nervous system has been recently shown to exert impact on gastric cancer directly and indirectly. Gastric cancer cells invade nerve fibers to induce outgrowth and branching of neural cells, and nerve fibers in turn infiltrate into tumor microenvironment to promote progression of gastric cancer. Additionally, the neuro-immune interaction also plays an important role in gastric cancer development. The interplay of nerves and gastric cancer is mediated by many nervous system-associated factors, which can not only be synthesized and released by both cancer cells and nerve terminals, but also participate in regulation of many aspects of gastric cancer such as cell proliferation, angiogenesis, metastasis and recurrence. Furthermore, clinical researches indicate that some of these factors are significant diagnosis and prognosis biomarkers for gastric cancer. Herein, we reviewed recent advances and future prospects of the interaction between nervous system and gastric cancer.

    更新日期:2019-10-22
  • The association between type of endocrine therapy and development of estrogen receptor-1 mutation(s) in patients with hormone-sensitive advanced breast cancer: A systematic review and meta-analysis of randomized and non-randomized trials
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-10-21
    Omar Najim, Sofie Seghers, Laurine Sergoynne, Hélène Van Gaver, Konstantinos Papadimitriou, Kristien Wouters, Xuan Bich Trinh, Manon T. Huizing, Wiebren Tjalma

    Background Breast cancer has, due to its high incidence, the highest mortality of cancer in women. The most common molecular type of breast cancer is the luminal subtype, which expresses estrogen and progesterone receptors and is typically treated with surgery and adjuvant endocrine therapy (ET). Estrogen receptor alpha (ERα), encoded by the estrogen receptor-1 (ESR1) gene, is expressed in approximately 70% of all breast cancers, and ET represents a major treatment modality in ERα-positive cancers. However, resistance to different ET evolves frequently, leading to disease progression or recurrence in ER+ breast cancer. Acquired mutations in the Ligand Binding Domain (LBD) of the ERα referred as ESR1 mutations; could be selected by ET itself leading to resistance over the course of ET therapy. Objective The goal of this review is to estimate the effect of Aromatase Inhibitors (AIs), Tamoxifen (TAM) and Fulvestrant (FUL) on the development of ESR1 mutations in hormone-sensitive advanced breast cancer. Methods A systematic review of qualitative studies published between January 1st, 2007 and March 1st, 2019 was conducted using the PubMed and Thomas Reuters Web of Science databases. Search terms included ESR1 mutations, estrogen receptor, breast cancer, recurrent, metastatic disease, aromatase inhibitors, fulvestrant and tamoxifen. Only full-text studies in English concerning the development of ESR1 mutations and their outcomes on disease progression were included. Selection of studies was performed using predefined data fields, taking study quality indicators into consideration. Inclusion criteria of the study populations were: Ghoncheh et al. (2016) [1] female patients above 18 years; Nielsen et al. (2011) [2] Estrogen-receptor positive (ER+) breast cancer in the advanced setting; Reinert et al. (2017) [3] previous exposure to endocrine therapy including SERDs (preferably Fulvestrant), SERMs (preferably Tamoxifen) or Aromatase Inhibitors. Results The current review enrolled 16 articles, including 4 multicentre double blinded RCTs and 12 cohorts and comprising a total of 2632 patients. The overall incidence rate of the ESR1 mutation was 24% (95% CI: 18%–31%). We observed that D538G was the most frequent ESR1 mutation. Several studies showed that prior endocrine therapy (AIs, TAM, FUL) could result in an ESR1 mutation and therapy resistance leading to disease progression or recurrence. Different mechanisms had been implied to explain the underlying ET resistance. One of the key findings of this work is the significant difference in ESR1 mutation incidence between patients with and without AI therapy (OR: 9.34, 95% CI: 3.28–26.62, P ≤.001). Conclusion ESR1 mutations are not uncommon phenomenon in patients with hormone-sensitive advanced breast cancer. There is a significant higher incidence rate of ESR1 mutations in patients with previous AI-containing therapeutic regimens, compared to those who received non-AI containing regimes. These ESR1 mutations could lead to the development of complete endocrine resistance to AI, whereas only partial resistance is seen in case of TAM or FUL.

    更新日期:2019-10-22
  • Long non-coding RNAs and nuclear factor-B crosstalk in cancer and other human diseases
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-10-19
    Subash C. Gupta, Nikee Awasthee, Vipin Rai, Srinivas Chava, Venugopal Gunda, Kishore B. Challagundla

    The regulation of the pleiotropic transcription factor, nuclear factor-κB (NF-κB) by miRNAs and proteins is extensively studied. More recently, the NF-κB signaling was also reported to be regulated by several long non-coding RNAs (lncRNAs) that constitute the major portion of the noncoding component of the human genome. The common NF-κB associated lncRNAs include NKILA, HOTAIR, MALAT1, ANRIL, Lethe, MIR31HG, and PACER. The lncRNA and NF-κB signaling crosstalk during cancer and other diseases such as cardiomyopathy, celiac disease, cerebral infarction, chronic kidney disease, diabetes mellitus, Kawasaki disease, pregnancy loss, and rheumatoid arthritis. Some NF-κB related lncRNAs can affect gene expression without modulating NF-κB signaling. Most of the lncRNAs with a potential to modulate NF-κB signaling are regulated by NF-κB itself suggesting a feedback regulation. The discovery of lncRNAs have provided a new type of regulation for the NF-κB signaling and thus could be explored for therapeutic interventions. The manner in which lncRNA and NF-κB crosstalk affects human pathophysiology is discussed in this review. The challenges associated with the therapeutic interventions of this crosstalk are also discussed.

    更新日期:2019-10-19
  • Functional analysis of deubiquitylating enzymes in tumorigenesis and development
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-08-23
    Ji Cheng, Jianping Guo, Brian J. North, Bin Wang, Chun-Ping Cui, Hongchang Li, Kaixiong Tao, Lingqiang Zhang, Wenyi Wei

    Deubiquitylating enzymes (DUBs) are proteases that remove the ubiquitin moiety from ubiquitylated substrates to antagonize the modification mediated by E3 ubiquitin ligases. Currently, DUBs have been found to play critical roles in the regulation of various physiological or pathological processes, such as embryogenesis, immune homeostasis, tumorigenesis and neurodegenerative diseases. Accumulating evidences have suggested that different DUBs exert distinct function such as oncogenic, tumor-suppressive or context-dependent roles in tumorigenesis, mainly by affecting the protein stability, enzymatic activity or subcellular localization of its substrates. Importantly, multiple potent inhibitors targeting the enzymatic activity of oncogenic DUBs have been developed and show promising anti-cancer efficacy in preclinical models. Thus, exploring the unique role of DUB enzymes and their downstream effectors will provide novel insights into the molecular basis of cancer development. Here, we review and summarize recent progress on DUB functional annotation, as well as its biochemical regulation, to provide a better understanding for cancer therapies by targeting DUBs.

    更新日期:2019-08-25
  • The tumor immune microenvironment in gastroenteropancreatic neuroendocrine neoplasms
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-08-20
    Wu-Hu Zhang, Wen-Quan Wang, He-Li Gao, Xian-Jun Yu, Liang Liu

    Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a group of rare tumors that are increasing in prevalence. The complex tumor immune microenvironment (TIME) plays an important role in tumor development and the response to immunotherapy but is poorly understood. In this review, the components of the TIME are described in detail, including discussion about infiltrating immune cells, the immune checkpoint system, the cytokine and chemokine milieu, and immunomodulatory factors. Moreover, a comparison between TIMEs among different types of GEP-NENs and the interplay among the TIME, tumor cells, and the stromal microenvironment is described. Novel treatment options for GEP-NENs and potential biomarkers for the immune response are also characterized. We provide a comprehensive generalized review of the TIME that can inform GEP-NEN treatment strategies.

    更新日期:2019-08-21
  • Mechanisms of acquired tumor drug resistance
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-08-20
    Svetlana N. Aleksakhina, Aniruddh Kashyap, Evgeny N. Imyanitov

    Systemic therapy often results in the reduction of tumor size but rarely succeeds in eradicating all cancer cells. Drug efflux, persistence of cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT) and down-regulation of apoptosis are the most known general causes of therapy failure. Tumor escape from targeted compounds often involves pathway-specific mechanisms, which result in the restoration of the affected signaling cascade. The acquisition of drug resistance is mediated by mutations, changes in gene expression, alternative splicing, post-translational protein modifications, etc. Development of resistance to therapy may not necessary involve the emergence of new tumor clones: multiple studies demonstrate that even chemonaive neoplasms already have a small population of cells, which are capable of surviving therapeutic pressure and facilitating the disease progression. Use of combinations of cancer drugs, sequential therapy, adaptive therapy and topical ablation of drug-resistant malignant lumps may help to prolong the time to treatment failure. Many studies on mechanisms of drug resistance rely on the use of cell cultures and animal models. The development of approaches that allow efficient monitoring of the evolution of tumor phenotype in clinical setting presents a challenge.

    更新日期:2019-08-20
  • Cell death in photodynamic therapy: From oxidative stress to anti-tumor immunity
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-08-08
    Claire Donohoe, Mathias O. Senge, Luís G. Arnaut, Lígia C. Gomes-da-Silva

    Photodynamic therapy is a promising approach for cancer treatment that relies on the administration of a photosensitizer followed by tumor illumination. The generated oxidative stress may activate multiple mechanism of cell death which are counteracted by cells through adaptive stress responses that target homeostasis rescue. The present renaissance of PDT was leveraged by the acknowledgment that this therapy has an immediate impact locally, in the illumination volume, but that subsequently it may elicit immune responses with systemic impact. The investigation of the mechanisms of cell death under the oxidative stress of PDT is of paramount importance to understand how the immune system is activated and, ultimately, to make PDT a more appealing/relevant therapeutic option.

    更新日期:2019-08-09
  • From squamous intraepithelial lesions to cervical cancer: Circulating microRNAs as potential biomarkers in cervical carcinogenesis
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-08-06
    Fernanda Costa Brandão Berti, Amanda Salviano-Silva, Helen Cristina Beckert, Karen Brajão de Oliveira, Gabriel Adelman Cipolla, Danielle Malheiros
    更新日期:2019-08-07
  • Microbial carcinogenesis: Lactic acid bacteria in gastric cancer
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-08-05
    Karla Vinasco, Hazel M. Mitchell, Nadeem O. Kaakoush, Natalia Castaño-Rodríguez

    While Helicobacter pylori is a fundamental risk factor, gastric cancer (GC) aetiology involves combined effects of microbial (both H. pylori and nonH. pylori), host and environmental factors. Significant differences exist between the gastric microbiome of those with gastritis, intestinal metaplasia and GC, suggesting that dysbiosis in the stomach is dynamic and correlates with progression to GC. Most notably, a consistent increase in abundance of lactic acid bacteria (LAB) has been observed in GC patients including Streptococcus, Lactobacillus, Bifidobacterium and Lactococcus. This review summarises how LAB can influence GC by a number of mechanisms that include supply of exogenous lactate —a fuel source for cancer cells that promotes inflammation, angiogenesis, metastasis, epithelial-mesenchymal transition and immune evasion—, production of reactive oxygen species and N-nitroso compounds, as well as anti-H. pylori properties that enable colonization by other nonH. pylori carcinogenic pathobionts.

    更新日期:2019-08-06
  • Novel insights into breast cancer progression and metastasis: A multidisciplinary opportunity to transition from biology to clinical oncology
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-07-23
    Manuel Scimeca, Nicoletta Urbano, Rita Bonfiglio, Andrea Duggento, Nicola Toschi, Orazio Schillaci, Elena Bonanno
    更新日期:2019-07-23
  • Sodium homeostasis in the tumour microenvironment
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-07-23
    Theresa K. Leslie, Andrew D. James, Fulvio Zaccagna, James T. Grist, Surrin Deen, Aneurin Kennerley, Frank Riemer, Joshua D. Kaggie, Ferdia A. Gallagher, Fiona J. Gilbert, William J. Brackenbury

    The concentration of sodium ions (Na+) is raised in solid tumours and can be measured at the cellular, tissue and patient levels. At the cellular level, the Na+ gradient across the membrane powers the transport of H+ ions and essential nutrients for normal activity. The maintenance of the Na+ gradient requires a large proportion of the cell’s ATP. Na+ is a major contributor to the osmolarity of the tumour microenvironment, which affects cell volume and metabolism as well as immune function. Here, we review evidence indicating that Na+ handling is altered in tumours, explore our current understanding of the mechanisms that may underlie these alterations and consider the potential consequences for cancer progression. Dysregulated Na+ balance in tumours may open opportunities for new imaging biomarkers and re-purposing of drugs for treatment.

    更新日期:2019-07-23
  • Fibroblasts in cancer: Defining target structures for therapeutic intervention
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-06-29
    Maximilian Boesch, Florent Baty, Holger Rumpold, Sieghart Sopper, Dominik Wolf, Martin H. Brutsche

    The functional importance of the tumor stroma for cancer growth and progression is increasingly recognized, but has not resulted in notable therapeutic developments yet. Within the mesenchymal tumor microenvironment, cancer-associated fibroblasts take the center stage and fuel tumor progression in various ways including malignant cell potentiation, immune regulation and fibrosis. However, recent studies have demonstrated pronounced heterogeneity of the fibroblastic tumor stroma, which comprises a plethora of individual cell subsets with varying phenotypes and functions, some of which suppress malignant growth through immune engagement or crosstalk with the tumor vasculature. This article summarizes the various levels at which the fibroblastic tumor stroma may impact cancer progression and highlights potential target structures for future therapeutic intervention(s).

    更新日期:2019-07-01
  • Comprehensive elaboration of database resources utilized in next-generation sequencing-based tumor somatic mutation detection
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-06-29
    Peng Gao, Rui Zhang, Jinming Li

    The rapid evolution of next-generation sequencing (NGS)-based tumor genomic profile detection and the emergence of molecularly targeted therapies have enabled precision oncology. In NGS-based analysis, various types of databases have been developed to perform different functions. However, many problems still exist when using these public databases. Therefore, it is important to better understand the characteristics and limitations of each database and have them complement each other to provide useful clinical evidence for NGS testing. In this review, we elaborate on the important role of databases and their concrete applications in NGS-based somatic mutation detection. We introduce the typically used databases for sequence alignment, variant filtration, and variant interpretation, and compare the differences between the databases with similar functions. Subsequently, we determine the limitations of each database and provide the corresponding solutions. Furthermore, we present an overview diagram to clearly illustrate the database used in the entire NGS-based somatic mutation detection pipeline.

    更新日期:2019-07-01
  • Metastasis as a systemic disease: molecular insights and clinical implications
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-06-14
    Maša Alečković, Sandra S. McAllister, Kornelia Polyak

    Metastasis is a complex systemic disease that develops as a result of interactions between tumor cells and their local and distant microenvironments. Local and systemic immune-related changes play especially critical roles in limiting or enabling the development of metastatic disease. Although anti-tumor immune responses likely eliminate most early primary and metastatic lesions, factors secreted by cancer or stromal cells in the primary tumor can mobilize and activate cells in distant organs in a way that promotes the outgrowth of disseminated cancer cells into macrometastatic lesions. Therefore, the prevention, detection, and effective treatment of metastatic disease require a deeper understanding of the systemic effects of primary tumors as well as predisposing hereditary and acquired host factors including chronic inflammatory conditions. The success of immunotherapy in a subset of cancer patients is an example of how modulating the microenvironment and tumor-immune cell interactions can be exploited for the effective eradiation of even advanced-stage tumors. Here, we highlight emerging insights and clinical implications of cancer as a systemic disease.

    更新日期:2019-06-14
  • FLT3 overexpression in acute leukaemias: New insights into the search for molecular mechanisms
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-06-12
    Caroline Pires Poubel, Marcela B. Mansur, Mariana Boroni, Mariana Emerenciano

    FLT3 overexpression is a recurrent event in various acute leukaemia subtypes. This transcriptional deregulation is important to define the prognostic risk for many patients. Of note, the molecular mechanisms leading to this gene upregulation are unknown for a substantial number of cases. In this Mini-Review, we highlight the role of FLT3 overexpression in acute leukaemia and discuss emerging mechanisms accounting for this upregulation. The benefits of using targeted therapy are also addressed in the overexpression context, posing other therapeutic possibilities based on state-of-the-art knowledge that could be considered by future research.

    更新日期:2019-06-13
  • Bacterial biofilms as a potential contributor to mucinous colorectal cancer formation
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-06-12
    Shan Li, Maikel P. Peppelenbosch, Ron Smits

    A prominent mucinous phenotype is observed in 10–15% of all colorectal cancers (CRCs). They are associated with a proximal location, and more commonly observed among tumors with mismatch repair defects and a promoter CpG methylator phenotype. However, none of these features has been clearly linked mechanistically to this mucinous subtype. Here, we propose that bacterial biofilms could represent a currently unappreciated contributor to mucinous CRC formation. The colonic microbiome and biofilms in particular, are emerging as important factors in tumor initiation and progression. Intriguingly, biofilms preferentially accompany proximal tumors, suggesting that there may be a direct mechanistic link with mucinous CRCs.

    更新日期:2019-06-12
  • Neuroendocrine regulation of cholangiocarcinoma: A status quo review
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-05-30
    Meng Sha, Jie Cao, Han-yong Sun, Ying Tong, Qiang Xia

    Increasing studies have demonstrated that neuroendocrine system is involved in the development and progression of cholangiocarcinoma. The neuroendocrine hormones, neurotransmitters and neuropeptides regulate cholangiocarcinoma via affecting pathophysiology of tumor cells. The developing interaction and interplay between neuroendocrine-associated factors and tumor cells provide novel insights into neural control of tumorigenesis and reveal potential therapeutic effect on patients with cholangiocarcinoma. Herein we reviewed the latest findings and achievements which demonstrate the close interactions between neuroendocrine regulation and progression of cholangiocarcinoma. Also, future therapeutic approaches targeting neuroendocrine-associated factors are discussed which may help improve management and treatment of cholangiocarcinoma.

    更新日期:2019-05-31
  • From genetics to signaling pathways: molecular pathogenesis of esophageal adenocarcinoma
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-05-30
    Ravindran Caspa Gokulan, Monica T. Garcia-Buitrago, Alexander I. Zaika

    Esophageal adenocarcinoma (EAC) has one of the fastest rising incidence rates in the U.S. and many other Western countries. One of the unique risk factors for EAC is gastroesophageal reflux disease (GERD), a chronic digestive condition in which acidic contents from the stomach, frequently mixed with duodenal bile, enter the esophagus resulting in esophageal tissue injury. At the cellular level, progression to EAC is underlined by continuous DNA damage caused by reflux and chronic inflammatory factors that increase the mutation rate and promote genomic instability. Despite recent successes in cancer diagnostics and treatment, EAC remains a poorly treatable disease. Recent research has shed new light on molecular alterations underlying progression to EAC and revealed novel treatment options. This review focuses on the genetic and molecular studies of EAC. The molecular changes that occur during the transformation of normal Barrett’s esophagus to esophageal adenocarcinoma are also discussed.

    更新日期:2019-05-31
  • Divergent roles of Plexin D1 in Cancer
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-05-30
    Sneha Vivekanandhan, Debabrata Mukhopadhyay

    Plexin D1 belongs to a family of transmembrane proteins called plexins. It was characterized as a receptor for semaphorins and is known to be essential for axonal guidance and vascular patterning. Mutations in Plexin D1 have been implicated in pathologic conditions such as truncus arteriosus and Möbius syndrome. Emerging data show that expression of Plexin D1 is deregulated in several cancers; it can support tumor development by aiding tumor angiogenesis and metastasis; and conversely, it can act as a dependence receptor and stimulate cell death in the absence of its canonical ligand, semaphorin 3E. The role of Plexin D1 in tumor development and progression is thereby garnering research interest for its potential as a biomarker and as a therapeutic target. In this review, we describe its discovery, structure, mutations, role in cancer, and therapeutic potential.

    更新日期:2019-05-31
  • Gluconeogenesis in cancer cells – Repurposing of a starvation-induced metabolic pathway?
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-05-30
    Gabriele Grasmann, Elisabeth Smolle, Horst Olschewski, Katharina Leithner

    Cancer cells constantly face a fluctuating nutrient supply and interference with adaptive responses might be an effective therapeutic approach. It has been discovered that in the absence of glucose, cancer cells can synthesize crucial metabolites by expressing phosphoenolpyruvate carboxykinase (PEPCK, PCK1 or PCK2) using abbreviated forms of gluconeogenesis. Gluconeogenesis, which in essence is the reverse pathway of glycolysis, uses lactate or amino acids to feed biosynthetic pathways branching from glycolysis. PCK1 and PCK2 have been shown to be critical for the growth of certain cancers. In contrast, fructose-1,6-bisphosphatase 1 (FBP1), a downstream gluconeogenesis enzyme, inhibits glycolysis and tumor growth, partly by non-enzymatic mechanisms. This review sheds light on current knowledge of cancer cell gluconeogenesis and its role in metabolic reprogramming, cancer cell plasticity, and tumor growth.

    更新日期:2019-05-31
  • Clinical validity of saliva and novel technology for cancer detection
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-05-30
    Karolina Elżbieta Kaczor-Urbanowicz, Fang Wei, Shannon Liu Rao, Jinseok Kim, Heebum Shin, Jordan Cheng, Michael Tu, David T.W. Wong, Yong Kim

    Cancer, a local disease at an early stage, systemically evolves as it progresses by triggering alterations in surrounding microenvironment, disturbing immune surveillance and further disseminating its molecular contents into circulation. This pathogenic characteristic of cancer makes the use of biofluids such as blood/serum/plasma, urine, tear and cerebrospinal fluids credible surrogates harboring tumor tissue-derived molecular alterations for the detection of cancer. Most importantly, a number of recent reports have credentialed the clinical validity of saliva for the detection of systemic diseases including cancers. In this review, we discussed the validity of saliva as credible biofluid and clinical sample type for the detection of cancers. We have presented the molecular constituents of saliva that could mirror the systemic status of our body and recent findings of salivaomics associated with cancers. Recently, liquid biopsy to detect cancer-derived circulating tumor DNA has emerged as a credible cancer-detection tool with potential benefits in screening, diagnosis and also risk management of cancers. We have further presented the clinical validity of saliva for liquid biopsy of cancers and a new technology platform based on electrochemical detection of cancer-derived ctDNA in saliva with superior sensitivity and point-of-care potential. The clinical utilities of saliva for the detection of cancers have been evidenced, but biological underpinning on the existence of molecular signatures of cancer-origin in saliva, such as via exosomal distribution, should be addressed in detail.

    更新日期:2019-05-31
  • Defective mitosis-linked DNA damage response and chromosomal instability in liver cancer
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-05-29
    Maryam Tahmasebi Birgani, Hossein Ansari, Vinicio Carloni

    Hepatocellular carcinoma (HCC), the most common form of liver cancer, represents a health problem in hepatic viruses-eradicating era because obesity, type 2 diabetes, and nonalcoholic steatohepatitis (NASH) are considered emerging pathogenic factors. Metabolic disorders underpin mitotic errors that lead to numerical and structural chromosome aberrations in a significant proportion of cell divisions. Here, we review that genomically unstable HCCs show evidence for a paradoxically DNA damage response (DDR) which leads to ongoing chromosome segregation errors. The understanding of DDR induced by defective mitoses is crucial to our ability to develop or improve liver cancer therapeutic strategies.

    更新日期:2019-05-31
  • Targeting PI3K signaling in cancer: Challenges and advances
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-04-01
    Maria Chiara De Santis, Federico Gulluni, Carlo Cosimo Campa, Miriam Martini, Emilio Hirsch

    The key role of phosphoinositide 3-kinase (PI3K) pathway in different cellular processes and several disorders, together with the presence of targetable proteins, opened the way to promising studies for the development of small molecule inhibitors. Despite the high expectation, the shift of PI3K inhibitors to the clinic met several limitations due to the emergence of dose-limiting, on-target adverse effects. In this review, we will summarize the main issues and recent advances in PI3K inhibitors clinical trials. The effort to develop isoform-specific inhibitors, together with novel therapeutic strategies aimed at reducing the toxicity and adverse effects, opened a new promising era for PI3K inhibitors. In addition, we will focus on the recent emergence of class II and III PI3K inhibitors, which helped to define their class I non-redundant role.

    更新日期:2019-05-16
  • Atomic force microscopy-based cancer diagnosis by detecting cancer-specific biomolecules and cells
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-04-02
    Taeyun Kwon, Sundaram Gunasekaran, Kilho Eom

    Atomic force microscopy (AFM) has recently attracted much attention due to its ability to analyze biomolecular interactions and to detect certain biomolecules, which play a crucial role in disease expression. Despite recent studies reporting AFM imaging for the analyses of biomolecules, the application of AFM-based cancer-specific biomolecule/cell detection has remained largely underexplored, especially for the early diagnosis of cancer. In this paper, we review the recent attempts, including our efforts, to analyze and detect cancer-specific biomolecules and cancer cells. We particularly focus on two AFM-based cancer diagnosis techniques: (i) AFM imaging-based biomolecular and cellular detection, (ii) AFM cantilever-based biomolecular sensing and cell analysis. It is shown that AFM-based biomolecular detection has been applied for not only early diagnosing cancer, by measuring the minute amount of cancer-specific proteins, but also monitoring of cancer progression, by correlating the amount of cancer-specific proteins with the progression of cancer. In addition, AFM-based cell imaging and detection have been employed for diagnosing cancer, by detecting cancerous cells in tissue, as well as understanding cancer progression, by characterizing the dynamics of cancer cells. This review, therefore, highlights AFM-based biomolecule/cell detection, which will pave the way for developing a fast and point-of-care diagnostic system for biomedical applications.

    更新日期:2019-05-16
  • Targeting the mTOR regulatory network in hepatocellular carcinoma: Are we making headway?
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-04-02
    Xiang-Nan Yu, Hong Chen, Tao-Tao Liu, Jian Wu, Ji-Min Zhu, Xi-Zhong Shen

    The mechanistic target of rapamycin (mTOR) pathway coordinates organismal growth and homeostasis in response to growth factors, nutrients, and cellular energy stage. The pathway regulates several major cellular processes and is implicated in various pathological conditions, including hepatocellular carcinoma (HCC). This review summarizes recent advances of the mTOR pathway, highlights the potential of the mTOR pathway as a therapeutic target, and explores clinical trials targeting the mTOR pathway in HCC. Although the review focuses on the mTOR pathway involved in HCC, more comprehensive discussions (eg, developing a rational design for future trials targeting the mTOR pathway) are also applicable to other tumors.

    更新日期:2019-05-16
  • The power of small changes: Comprehensive analyses of microbial dysbiosis in breast cancer
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-04-11
    Sheetal Parida, Dipali Sharma

    Disparate occurrence of breast cancer remains an intriguing question since only a subset of women with known risk factors develop cancer. Recent studies suggest an active role of local and distant microbiota in breast cancer initiation, progression, and overall prognosis. A dysbiotic microbiota predisposes the body to develop cancer by inducing genetic instability, initiating DNA damage and proliferation of the damaged progeny, eliciting favorable immune response, metabolic dysregulation and altered response to therapy. In this review, we present our analyses of the existing datasets and discuss the local dysbiosis observed in breast cancer patients and different aspects of breast carcinogenesis that can be potentially influenced by local breast microbiota. Striking differences between microbial community compositions in breast of cancer patients compared to healthy individuals were noted. Differences in microbiome were also apparent between benign and malignant disease and between nipple aspirate fluid of healthy individuals and breast survivors. We also discuss the identification of distinct bacterial, fungal, viral as well as parasite signatures for breast cancer. These microbes are capable of producing numerous secondary metabolites that can act as signaling mediators effecting breast cancer progression. We review how microbes potentially alter response to therapy affecting drug metabolism, pharmacokinetics, anti-tumor effects and toxicity. In conclusion, breast harbors a community of microbes that can communicate with the host cells inducing downstream signaling pathways and modulating various aspects of breast cancer growth and metastatic progression and an improved understanding of microbial dysbiosis can potentially reduce breast cancer risk and improve outcomes of breast cancer patients. The human microbiome, now referred to as, the “forgotten organ” contains a metagenome that is 100-fold more diverse compared to the human genome, thereby, is critically associated with human health [1,2]. With the revelations of the human microbiome project and advent of deep sequencing techniques, a plethora of information has been acquired in recent years. Body sites like stomach, bladder and lungs, once thought to be sterile, are now known to harbor millions of indigenous microbial species. Approximately 80% of the healthy microbiome consists of Firmicutes and Bacteroidetes accompanied by Verrucomicrobia, Actinobacteria, Proteobacteria, Tenericutes and Cyanobacteria [[2], [3], [4], [5], [6], [7]]. The role of microbiome in diabetes, obesity and even neurodegenerative diseases was greatly appreciated in the last decade [1,[7], [8], [9], [10], [11], [12], [13], [14]] and now it has been established that microbiome significantly contributes to many organ specific cancers [1,15,16].

    更新日期:2019-05-16
  • The small members of the JMJD protein family: Enzymatic jewels or jinxes?
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-04-26
    Sangphil Oh, Sook Shin, Ralf Janknecht

    Jumonji C domain-containing (JMJD) proteins are mostly epigenetic regulators that demethylate histones. However, a hitherto neglected subfamily of JMJD proteins, evolutionarily distant and characterized by their relatively small molecular weight, exerts different functions by hydroxylating proteins and RNA. Recently, unsuspected proteolytic and tyrosine kinase activities were also ascribed to some of these small JMJD proteins, further increasing their enzymatic versatility. Here, we discuss the ten human small JMJD proteins (HIF1AN, HSPBAP1, JMJD4, JMJD5, JMJD6, JMJD7, JMJD8, RIOX1, RIOX2, TYW5) and their diverse physiological functions. In particular, we focus on the roles of these small JMJD proteins in cancer and other maladies and how they are modulated in diseased cells by an altered metabolic milieu, including hypoxia, reactive oxygen species and oncometabolites. Because small JMJD proteins are enzymes, they are amenable to inhibition by small molecules and may represent novel targets in the therapy of cancer and other diseases.

    更新日期:2019-05-16
  • Nanoparticle-mediated targeted drug delivery for breast cancer treatment
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-04-26
    Piumi Y. Liyanage, Sajini D. Hettiarachchi, Yiqun Zhou, Allal Ouhtit, Elif S. Seven, Cagri Y. Oztan, Emrah Celik, Roger M. Leblanc
    更新日期:2019-05-16
  • Exosomes in cancer development, metastasis, and immunity
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-04-30
    Lin Zhang, Dihua Yu

    Exosomes play essential roles in intercellular communications. The exosome was discovered in 1983, when it was found that reticulocytes release 50-nm small vesicles carrying transferrin receptors into the extracellular space. Since then, our understanding of the mechanism and function of the exosome has expanded exponentially that has transformed our perspective of inter-cellular exchanges and the molecular mechanisms that underlie disease progression. Cancer cells generally produce more exosomes than normal cells, and exosomes derived from cancer cells have a strong capacity to modify both local and distant microenvironments. In this review, we summarize the functions of exosomes in cancer development, metastasis, and anti-tumor or pro-tumor immunity, plus their application in cancer treatment and diagnosis/prognosis. Although the exosome field has rapidly advanced, we still do not fully understand the regulation and function of exosomes in detail and still face many challenges in their clinical application. Continued discoveries in this field will bring novel insights on intercellular communications involved in various biological functions and disease progression, thus empowering us to effectively tackle accompanying clinical challenges.

    更新日期:2019-05-16
  • Drug repurposing in oncology: Compounds, pathways, phenotypes and computational approaches for colorectal cancer
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-04-26
    Patrycja Nowak-Sliwinska, Leonardo Scapozza, Ariel Ruiz i Altaba

    The strategy of using existing drugs originally developed for one disease to treat other indications has found success across medical fields. Such drug repurposing promises faster access of drugs to patients while reducing costs in the long and difficult process of drug development. However, the number of existing drugs and diseases, together with the heterogeneity of patients and diseases, notably including cancers, can make repurposing time consuming and inefficient. The key question we address is how to efficiently repurpose an existing drug to treat a given indication. As drug efficacy remains the main bottleneck for overall success, we discuss the need for machine-learning computational methods in combination with specific phenotypic studies along with mechanistic studies, chemical genetics and omics assays to successfully predict disease-drug pairs. Such a pipeline could be particularly important to cancer patients who face heterogeneous, recurrent and metastatic disease and need fast and personalized treatments. Here we focus on drug repurposing for colorectal cancer and describe selected therapeutics already repositioned for its prevention and/or treatment as well as potential candidates. We consider this review as a selective compilation of approaches and methodologies, and argue how, taken together, they could bring drug repurposing to the next level.

    更新日期:2019-05-16
  • Achalasia and associated esophageal cancer risk: What lessons can we learn from the molecular analysis of Barrett's–associated adenocarcinoma?
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-05-04
    K. Nesteruk, M.C.W. Spaander, I. Leeuwenburgh, M.P. Peppelenbosch, G.M. Fuhler

    Idiopathic achalasia and Barrett's esophagus (BE) are preneoplastic conditions of the esophagus. BE increases the risk of esophageal adenocarcinoma (EAC), while achalasia is associated with both EAC and esophageal squamous cell carcinoma (ESCC). However, while the molecular mechanisms underlying the transformation of esophageal epithelial cells in BE are relatively well characterized, less is known regarding these processes in achalasia. Nevertheless, both conditions are associated with chronic inflammation and BE can occur in achalasia patients, and it is likely that similar processes underlie cancer risk in both diseases. The present review will discuss possible lessons that we can learn from the molecular analysis of BE for the study of achalasia-associated cancer and contrast findings in BE with those in achalasia. First, we will describe cellular fate during development of BE, EAC, and ESCC, and consider the inflammatory status of the epithelial barrier in BE and achalasia in terms of its contribution to carcinogenesis. Next, we will summarize current data on genetic alterations and molecular pathways involved in these processes. Lastly, the plausible role of the microbiota in achalasia-associated carcinogenesis and its contribution to abnormal lower esophageal sphincter (LES) functioning, the maintenance of chronic inflammatory status and influence on the esophageal mucosa through carcinogenic by-products, will be discussed.

    更新日期:2019-05-16
  • The role of inflammatory programmed cell death in gastrointestinal cancer and immune responses to intestinal microbial infection
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-05-03
    Cheng-Bei Zhou, Jing-Yuan Fang

    Inflammatory programmed cell death, also called pyroptosis, is mediated by multiple inflammasomes which can recognize danger signals and activate the secretion of pro-inflammatory cytokines like IL-181 and IL-1β.2 It can induce cancer cell death within the gastrointestinal tract. NLRs,3 AIM2,4 GSDM5 family play important roles in pyroptosis signaling pathways in intestinal cancer such as gastric cancer, colitis-associated colorectal cancer and esophageal cancer, etc. Furthermore, several inflammasomes are elucidated to be involved in mucosal innate immune responses and modulate specific enteric pathogens infection. Precise modulation of inflammasome activation and exploration of potential diagnostic markers can contribute to the diagnosis, prevention and treatment of intestinal tumors and inflammatory or infectious disorders in human patients in the near future.

    更新日期:2019-05-16
  • The AP-1 transcriptional complex: Local switch or remote command?
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-04-26
    Bejjani Fabienne, Evanno Emilie, Zibara Kazem, Piechaczyk Marc, Jariel-Encontre Isabelle

    The ubiquitous family of AP-1 dimeric transcription complexes is involved in virtually all cellular and physiological functions. It is paramount for cells to reprogram gene expression in response to cues of many sorts and is involved in many tumorigenic processes. How AP-1 controls gene transcription has largely remained elusive till recently. The advent of the “omics” technologies permitting genome-wide studies of transcription factors has however changed and improved our view of AP-1 mechanistical actions. If these studies confirm that AP-1 can sometimes act as a local transcriptional switch operating in the vicinity of transcription start sites (TSS), they strikingly indicate that AP-1 principally operates as a remote command binding to distal enhancers, placing chromatin architecture dynamics at the heart of its transcriptional actions. They also unveil novel constraints operating on AP-1, as well as novel mechanisms used to regulate gene expression via transcription-pioneering-, chromatin-remodeling- and chromatin accessibility maintenance effects.

    更新日期:2019-05-16
  • Immune checkpoint blockade and its combination therapy with small-molecule inhibitors for cancer treatment
    BBA Rev. Cancer (IF 6.887) Pub Date : 2018-12-31
    Manni Wang, Yu Liu, Yuan Cheng, Yuquan Wei, Xiawei Wei

    Initially understood for its physiological maintenance of self-tolerance, the immune checkpoint molecule has recently been recognized as a promising anti-cancer target. There has been considerable interest in the biology and the action mechanism of the immune checkpoint therapy, and their incorporation with other therapeutic regimens. Recently the small-molecule inhibitor (SMI) has been identified as an attractive combination partner for immune checkpoint inhibitors (ICIs) and is becoming a novel direction for the field of combination drug design. In this review, we provide a systematic discussion of the biology and function of major immune checkpoint molecules, and their interactions with corresponding targeting agents. With both preclinical studies and clinical trials, we especially highlight the ICI + SMI combination, with its recent advances as well as its application challenges.

    更新日期:2019-03-13
  • A critical review of the role of M2PYK in the Warburg effect
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-01-29
    Robert A. Harris, Aron W. Fenton

    It is becoming generally accepted in recent literature that the Warburg effect in cancer depends on inhibition of M2PYK, the pyruvate kinase isozyme most commonly expressed in tumors. We remain skeptical. There continues to be a general lack of solid experimental evidence for the underlying idea that a bottle neck in aerobic glycolysis at the level of M2PYK results in an expanded pool of glycolytic intermediates (which are thought to serve as building blocks necessary for proliferation and growth of cancer cells). If a bottle neck at M2PYK exists, then the remarkable increase in lactate production by cancer cells is a paradox, particularly since a high percentage of the carbons of lactate originate from glucose. The finding that pyruvate kinase activity is invariantly increased rather than decreased in cancer undermines the logic of the M2PYK bottle neck, but is consistent with high lactate production. The “inactive” state of M2PYK in cancer is often described as a dimer (with reduced substrate affinity) that has dissociated from an active tetramer of M2PYK. Although M2PYK clearly dissociates easier than other isozymes of pyruvate kinase, it is not clear that dissociation of the tetramer occurs in vivo when ligands are present that promote tetramer formation. Furthermore, it is also not clear whether the dissociated dimer retains any activity at all. A number of non-canonical functions for M2PYK have been proposed, all of which can be challenged by the finding that not all cancer cell types are dependent on M2PYK expression. Additional in-depth studies of the Warburg effect and specifically of the possible regulatory role of M2PYK in the Warburg effect are needed.

    更新日期:2019-03-13
  • Combination therapies with HSP90 inhibitors against colorectal cancer
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-01-30
    Kushtrim Kryeziu, Jarle Bruun, Tormod K. Guren, Anita Sveen, Ragnhild A. Lothe

    Oncogene stability and homeostasis mediated by the HSP90 chaperone is a crucial protection trait of cancer cells. Therefore, HSP90 represents an attractive therapeutic target for many cancers, including colorectal cancer. Although monotherapy has limited clinical efficacy, preclinical and early-phase clinical studies indicate improved antitumor activity when HSP90 inhibitors are combined with chemotherapies or targeted agents. This may be further improved with a biomarker-guided approach based on oncogenic HSP90 clients, or stratification based on the consensus molecular subtypes of colorectal cancer, suggesting a synergistic activity with 5-fluorouracil in preclinical models of the chemorefractory mesenchymal subtype. Furthermore, HSP90 inhibition may activate mechanisms to turn non-immunogenic tumors hot and improve their recognition by the immune system, suggesting synergy with immune checkpoint blockade.

    更新日期:2019-03-13
  • Prostate cancer-specific hallmarks of amino acids metabolism: Towards a paradigm of precision medicine
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-01-29
    Vladislav Strmiska, Petr Michalek, Tomas Eckschlager, Marie Stiborova, Vojtech Adam, Sona Krizkova, Zbynek Heger

    So far multiple differences in prostate cancer-specific amino acids metabolism have been discovered. Moreover, attempts to utilize these alterations for prostate cancer diagnosis and treatment have been made. The prostate cancer metabolism and biosynthesis of amino acids are particularly focused on anaplerosis more than on energy production. Other crucial requirements on amino acids pool come from the serine, one‑carbon cycle, glycine synthesis pathway and folate metabolism forming major sources of interproducts for synthesis of nucleobases necessary for rapidly proliferating cells. Considering the lack of some amino acids biosynthetic pathways and/or their extraordinary importance for prostate cancer cells, there is a widespread potential for targeted therapeutic applications with no effect on non-malignant cells. This review summarizes the up-to-date knowledge of the importance of amino acids for prostate cancer pathogenesis with a special emphasis on potential applications of metabolic variabilities in the new oncologic paradigm of precision medicine.

    更新日期:2019-03-13
  • The role of necroptosis in cancer: A double-edged sword?
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-02-01
    Xia Qin, Dan Ma, Ye-xiong Tan, Hong-yang Wang, Zhenyu Cai

    Necroptosis is a programmed, caspase-independent cell death that is morphologically similar to necrosis. Unlike apoptosis, necroptosis evokes inflammatory responses by releasing damage-associated molecular patterns. Recent studies suggest that tumor undergoes necroptosis in vivo and necroptosis has pro- or anti-tumoral effects in cancer development and progression. Furthermore, triggering necroptosis in tumor cells has been explored as a potential therapeutic strategy against cancer. Here, we will review the recent research progress of necroptosis in conferring anti- or pro-tumoral effects and its potential application in cancer therapy.

    更新日期:2019-03-13
  • Reflections on depletion of tumor stroma in pancreatic cancer
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-02-06
    Wen-Quan Wang, Liang Liu, Jin-Zhi Xu, Xian-Jun Yu

    Pancreatic cancer characteristically has an extremely dense stroma, which facilitates chemoresistance by creating physical and biological barriers to therapeutic agents. Thus, stroma-depleting agents may enhance the delivery and efficacy of chemotherapy drugs. However, stroma-targeting therapy for pancreatic cancer is a double-edged sword, as the stroma can also inhibit tumor metastasis and malignancy. In-depth understanding of the critical role of the stroma in cancer metastasis may improve therapeutic approaches by allowing them to harness specific features of the stroma to treat pancreatic cancer.

    更新日期:2019-03-13
  • Targeting acidity in cancer and diabetes
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-01-30
    Robert J. Gillies, Christian Pilot, Yoshinori Marunaka, Stefano Fais

    While cancer is commonly described as “a disease of the genes”, it is also a disease of metabolism. Indeed, carcinogenesis and malignancy are highly associated with metabolic re-programming, and there is clinical evidence that interrupting a cancer's metabolic program can improve patients' outcomes. Notably, many of the metabolic adaptations observed in cancer are similar to the same perturbations observed in diabetic patients. For example, metformin is commonly used to reduce hyperglycemia in diabetic patients, and has been demonstrated to reduce cancer incidence. Treatment with PI3K inhibitors can induce hyperinsulinemia, which can blunt therapeutic efficacy if unchecked. While commonalities between metabolism in cancer and diabetes have been extensively reviewed, here we examine a less explored and emergent convergence between diabetic and cancer metabolism: the generation of lactic acid and subsequent acidification of the surrounding microenvironment. Extracellular lactic acidosis is integral in disease manifestation and is a negative prognostic in both disease states. In tumors, this results in important sequela for cancer progression including increased invasion and metastasis, as well as inhibition of immune surveillance. In diabetes, acidosis impacts the ability of insulin to bind to its receptor, leading to peripheral resistance and an exacerbation of symptoms. Thus, acidosis may be a relevant therapeutic target, and we describe three approaches for targeting: buffers, nanomedicine, and proton pump inhibitors.

    更新日期:2019-03-13
  • RLIP: An existential requirement for breast carcinogenesis
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-02-13
    Sharad S. Singhal, Ravi Salgia, Sulabh Singhal, David Horne, Sanjay Awasthi

    Breast cancer (BC) is the most common cancer among women worldwide. Due to its complexity in nature, effective BC treatment can encounter many challenges. The human RALBP1 gene encodes a 76-kDa splice variant protein, RLIP (ral-binding protein1, RalBP1), a stress-protective mercapturic acid pathway (MAP) transporter protein, that also plays a key role in regulating clathrin-dependent endocytosis (CDE) as a Ral effector. Growing evidence shows that targeting RLIP may be an effective strategy in cancer therapy, as RLIP is over-expressed in multiple cancers and is known to induce resistance to apoptosis and chemotherapeutic drugs. Recent studies demonstrated that RLIP is expressed in human BC tissues, as well as BC cell lines. Knockdown of RLIP resulted in apoptotic death of BC cells in vitro, and targeted inhibition and depletion of RLIP resulted in regression of BC in xenograft studies of nude mice. Signaling studies showed that RLIP depletion inhibited endocytosis and differentially regulated signaling to Akt, Myc, and ERK1/2. However, the proliferation and multi-specific transport mechanisms that promote RLIP-mediated cell death in BC are not well understood. In this review, we will discuss a missing but an essentially determining and connecting piece of the puzzle on the understanding of proliferation and transport mechanisms by focused analyses of the apoptotic, drug- and radiation-sensitivity regulated by RLIP, a stress-responsive non-ATP-binding cassette (ABC), high capacity MAP transporter, in breast cancer.

    更新日期:2019-03-13
  • Potential roles and targeted therapy of the CXCLs/CXCR2 axis in cancer and inflammatory diseases
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-01-29
    Yuan Cheng, Xue-lei Ma, Yu-quan Wei, Xia-Wei Wei

    The chemokine receptor CXCR2 and its ligands are implicated in the progression of tumours and various inflammatory diseases. Activation of the CXCLs/CXCR2 axis activates multiple signalling pathways, including the PI3K, p38/ERK, and JAK pathways, and regulates cell survival and migration. The CXCLs/CXCR2 axis plays a vital role in the tumour microenvironment and in recruiting neutrophils to inflammatory sites. Extensive infiltration of neutrophils during chronic inflammation is one of the most important pathogenic factors in various inflammatory diseases. Chronic inflammation is considered to be closely correlated with initiation of cancer. In addition, immunosuppressive effects of myeloid-derived suppressor cells (MDSCs) against T cells attenuate the anti-tumour effects of T cells and promote tumour invasion and metastasis. Over the last several decades, many therapeutic strategies targeting CXCR2 have shown promising results and entered clinical trials. In this review, we focus on the features and functions of the CXCLs/CXCR2 axis and highlight its role in cancer and inflammatory diseases. We also discuss its potential use in targeted therapies.

    更新日期:2019-03-13
  • Many ways to resistance: How melanoma cells evade targeted therapies
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-02-15
    Ines Kozar, Christiane Margue, Sonja Rothengatter, Claude Haan, Stephanie Kreis

    Melanoma is an aggressive malignancy originating from pigment-producing melanocytes. The development of targeted therapies (MAPK pathway inhibitors) and immunotherapies (immune checkpoint inhibitors) led to a substantial improvement in overall survival of patients. However, the long-term efficacy of such treatments is limited by side effects, lack of clinical effects and the rapidly emerging resistance to treatment. A number of molecular mechanisms underlying this resistant phenotype have already been elucidated. In this review, we summarise currently available treatment options for metastatic melanoma and the known resistance mechanisms to targeted therapies. A focus will be placed on “phenotype switching” as a mechanism and driver of drug resistance, together with an overview of novel approaches to circumvent resistance. A large body of recent data and literature suggests that tumour progression and phenotype switching could be better controlled and development of resistance prevented or at least delayed, by combining drugs targeting fast- and slow-proliferating cells.

    更新日期:2019-03-13
  • Rethinking pulmonary toxicity in advanced non-small cell lung cancer in the era of combining anti-PD-1/PD-L1 therapy with thoracic radiotherapy
    BBA Rev. Cancer (IF 6.887) Pub Date : 2019-02-28
    Mengqian Li, Lu Gan, Andrew Song, Jianxin Xue, You Lu

    The combination of programmed cell death 1/programmed cell death ligand 1 blockade and thoracic radiotherapy has become the new standard of care in the treatment of locally advanced non-small-cell lung cancer. The information regarding the pulmonary safety of such therapy remains limited to mostly retrospective studies and case reports with a small portion of data from prospective clinical trials. By analyzing the underlying mechanisms of interactions between radiation and immunotherapy from preclinical data and summarizing safety data from relevant clinical studies with pulmonary toxicity, we believe that longer and rigorous follow-up is warranted, to determine if the combination of such modalities is appropriate for patients without risking undue toxicity.

    更新日期:2019-03-13
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