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  • Organizing ‘Elements’: Facilitating Exocytosis and Promoting Metastasis
    Trends Cancer (IF 8.884) Pub Date : 2020-02-24
    Dominique C. Stephens; Dinari A. Harris

    For metastasis to occur, cancer cells must exocytose proteases, like matrix metalloproteinases (MMPs), that are key in extracellular matrix (ECM) degradation. Growing evidence suggests that cancer cells use distinct spatial and temporal clustering patterns or organizing ‘elements’ that facilitate secretory vesicle fusion and the subsequent exocytosis of proteins that contribute to metastasis.

    更新日期:2020-02-24
  • Identification of Antigenic Targets
    Trends Cancer (IF 8.884) Pub Date : 2020-02-20
    Hans-Peter Gerber; Leah V. Sibener; Luke J. Lee; Marvin H. Gee

    The ideal cancer target antigen (Ag) is expressed at high copy numbers on neoplastic cells, absent on normal tissues, and contributes to the survival of cancer cells. Despite significant investments in the identification of cell surface Ags, there is a paucity of targets that meet such ideal cancer target criteria. Recent clinical trials in patients with cancer treated with immune checkpoint inhibitors (ICIs) indicate that cluster of differentiation (CD)8+ T cells, by means of their T cell receptors (TCRs) recognizing intracellular targets presented as peptides in the context of human leukocyte antigen (peptide–human leukocyte antigen complex; pHLA) molecules on tumor cells, can mediate deep and long-lasting antitumor responses in patients with solid tumors. Therefore, pHLA-target Ags may represent the long sought-after, ideal targets for solid tumor targeting by high-potency oncology compounds.

    更新日期:2020-02-21
  • Mutagenesis by Microbe: the Role of the Microbiota in Shaping the Cancer Genome
    Trends Cancer (IF 8.884) Pub Date : 2020-02-20
    Maurice Barrett; Collette K. Hand; Fergus Shanahan; Thomas Murphy; Paul W. O’Toole

    Cancers arise through the process of somatic evolution fueled by the inception of somatic mutations. We lack a complete understanding of the sources of these somatic mutations. Humans host a vast repertoire of microbes collectively known as the microbiota. The microbiota plays a role in altering the tumor microenvironment and proliferation. In addition, microbes have been shown to elicit DNA damage which provides the driver for somatic mutations. An understanding of microbiota-driven mutational mechanisms would contribute to a more complete understanding of the origins of the cancer genome. Here, we review the modes by which microbes stimulate DNA damage and the effect of these phenomena upon the cancer genomic architecture, specifically in the form of mutational spectra and mutational signatures.

    更新日期:2020-02-20
  • Gap Junctions and Breast Cancer Dormancy
    Trends Cancer (IF 8.884) Pub Date : 2020-02-20
    Garima Sinha; Alejandra I. Ferrer; Caitlyn A. Moore; Yahaira Naaldijk; Pranela Rameshwar

    Breast cancer (BC) relapse, despite clinical advancement, remains one of the biggest issues in the field. Intercellular communication, specifically via connexin (Cx)-mediated gap junctions (GJs), play a key role in the long-term survival of these, treatment-resistant breast cancer stem cells (CSCs), allowing for relapse. Both basic and clinical evidence reveal dual roles for GJs, in tumor suppression, generally referred to as dormancy, and progression and metastasis. GJ intercellular communication (GJIC) can be mediated by multiple types of Cxs, depending on the organ to which the BC cells metastasize. This review expands on the differential expression of Cx-mediated GJIC between CSCs and niche cells within a given microenvironment.

    更新日期:2020-02-20
  • Circular RNAs in Cancer: Biogenesis, Function, and Clinical Significance
    Trends Cancer (IF 8.884) Pub Date : 2020-02-19
    Jiao Li; Dan Sun; Wenchen Pu; Jin Wang; Yong Peng

    Circular RNA (circRNA) is a class of single-stranded molecules with tissue/development-specific expression patterns. Unlike linear RNA, circRNA forms a covalently closed loop produced from ‘back-splicing’ of primary transcripts, conferring on them inherent resistance to exonucleolytic RNA decay. Increasing evidence demonstrates that many circRNAs exert important biological functions by acting as miRNA inhibitors (‘sponges’), protein ‘decoys’, or by encoding small peptides. Importantly, circRNAs are aberrantly expressed in cancer and play indispensable oncogenic or tumor suppressive roles during tumor development and progression. In this review, we summarize the biogenesis, turnover, and involvements of circRNAs in cancer and also discuss their potential as diagnostic biomarkers or therapeutic targets.

    更新日期:2020-02-20
  • Brachyury: Strategies for Drugging an Intractable Cancer Therapeutic Target
    Trends Cancer (IF 8.884) Pub Date : 2020-02-19
    Helena Robinson; Ramsay J. McFarlane; Jane A. Wakeman

    New approaches to drug discovery are unlocking enormous therapeutic potential residing in cancer-specific molecules. Brachyury is emerging as an exciting new drug target for the rare bone cancer chordoma. Here, recent advances targeting Brachyury in chordoma are discussed and how these might open doors to the targeting of other, more common cancer types.

    更新日期:2020-02-20
  • DNA-PK, Nuclear mTOR, and the Androgen Pathway in Prostate Cancer
    Trends Cancer (IF 8.884) Pub Date : 2020-02-18
    Vincent Giguère

    Androgen and its receptor (AR) are major drivers of prostate cancer (PCa), a leading cause of mortality in aging men. Thus, understanding the numerous mechanisms by which AR can promote the growth and proliferation of PCa cells and enable their escape from hormone-dependent therapies, eventually leading to metastasis and death of the patient, is essential to discover alternative therapeutic approaches. Recently, two structurally related members of the phosphatidylinositol 3-kinase-like protein kinase (PIKK) family, DNA-dependent protein kinase (DNA-PK) and mammalian target of rapamycin (mTOR), were shown to have a direct role in modulating AR activity on chromatin of PCa cells. In this review, the common features of DNA-PK and mTOR and the similarities in their noncanonical roles as transcription coregulators of the AR are highlighted. An outlook on how these findings could be translated into new approaches to manage and treat PCa is provided.

    更新日期:2020-02-20
  • Understanding the Cause and Consequence of Tumor Heterogeneity
    Trends Cancer (IF 8.884) Pub Date : 2020-02-13
    Subreen Khatib; Yotsawat Pomyen; Hien Dang; Xin Wei Wang

    Tumor heterogeneity is a large conundrum in cancer medicine, making most therapeutic interventions palliative rather than curative. Here we discuss the implications of how molecularly targeted therapies in solid malignancies that promote limited cancer cell death may in fact make tumors more heterogeneous, increase aggressive phenotypes, and thus worsen patient outcomes.

    更新日期:2020-02-20
  • PALB2 Genetic Variants: Can Functional Assays Assist Translation?
    Trends Cancer (IF 8.884) Pub Date : 2020-02-13
    Melissa C. Southey; Amanda Rewse; Tu Nguyen-Dumont

    PALB2 loss-of-function variants are associated with increased risk of breast and other cancers, but the clinical relevance of missense variants (MVs) remains uncertain. Recent findings reported by Wiltshire et al., Rodrigue et al., and Boonen et al. demonstrate that some MVs disrupt PALB2 function. This new information will support the clinical management of families who carry these MVs and inform their treatment.

    更新日期:2020-02-20
  • Nanotherapeutics for Immuno-Oncology: A Crossroad for New Paradigms
    Trends Cancer (IF 8.884) Pub Date : 2020-02-13
    Wantong Song; Manisit Das; Xuesi Chen

    With the rapid increase in the use of nanotechnology and immunotherapy for cancer management in the recent past, there are great implications for using nanotechnology in immuno-oncology. However, to deliver clinical success, the scientific and clinical rationale must be critically evaluated when applying nanotechnology to immuno-oncology challenges. This opinion article distinguishes between designing nanotherapeutics for immunotherapy and the past focus on the placement of chemotherapy agents in nanoparticles. We believe the integration of nanotechnology with cancer immunotherapy for nano-immunotherapeutics provides unique opportunities for both fields, paving the way for entirely new therapeutic paradigms. As a particular focus in our article, we envision the necessities and challenges of nanotechnology in the development of in situ cancer vaccines, immune checkpoint inhibitors, adoptive cell transfer, and bispecific antibody therapy.

    更新日期:2020-02-20
  • The Cancer Microbiome: Distinguishing Direct and Indirect Effects Requires a Systemic View
    Trends Cancer (IF 8.884) Pub Date : 2020-02-07
    Joao B. Xavier; Vincent B. Young; Joseph Skufca; Fiona Ginty; Traci Testerman; Alexander T. Pearson; Paul Macklin; Amir Mitchell; Ilya Shmulevich; Lei Xie; J. Gregory Caporaso; Keith A. Crandall; Nicole L. Simone; Filipa Godoy-Vitorino; Timothy J. Griffin; Katrine L. Whiteson; Heather H. Gustafson; Daniel J. Slade; Jennifer A. Wargo

    The collection of microbes that live in and on the human body – the human microbiome – can impact on cancer initiation, progression, and response to therapy, including cancer immunotherapy. The mechanisms by which microbiomes impact on cancers can yield new diagnostics and treatments, but much remains unknown. The interactions between microbes, diet, host factors, drugs, and cell–cell interactions within the cancer itself likely involve intricate feedbacks, and no single component can explain all the behavior of the system. Understanding the role of host-associated microbial communities in cancer systems will require a multidisciplinary approach combining microbial ecology, immunology, cancer cell biology, and computational biology – a systems biology approach.

    更新日期:2020-02-07
  • On Epigenetic Plasticity and Genome Topology
    Trends Cancer (IF 8.884) Pub Date : 2020-02-07
    Charalampos Lazaris; Iannis Aifantis; Aristotelis Tsirigos

    Mounting evidence links genetic lesions with genome topology alterations and aberrant gene activation. However, the role of epigenetic plasticity remains elusive. Emerging studies implicate DNA methylation, transcriptional elongation, long noncoding RNAs (lncRNAs), and CCCTC-binding factor (CTCF)–RNA interactions, but systematic approaches are needed to fully decipher the role of epigenetic plasticity in genome integrity and function.

    更新日期:2020-02-07
  • Hyperprogression and Immunotherapy: Fact, Fiction, or Alternative Fact?
    Trends Cancer (IF 8.884) Pub Date : 2020-02-06
    Jacob J. Adashek; Ishwaria M. Subbiah; Ignacio Matos; Elena Garralda; Arjun K. Menta; Dhakshina Moorthy Ganeshan; Vivek Subbiah

    Immunotherapy (IO) has altered the therapeutic landscape for multiple cancers. There are emerging data from retrospective studies on a subset of patients who do not benefit from IO, instead experiencing rapid progression with dramatic acceleration of disease trajectory, termed ‘hyperprogressive disease’ (HPD). The incidence of HPD ranges from 4% to 29% from the studies reported. Biological basis and mechanisms of HPD are currently being elucidated, with one theory involving the Fc region of antibodies. Another group has shown EGFR and MDM2/MDM4 amplifications in patients with HPD. This phenomenon has polarized oncologists who debate that this could still reflect the natural history of the disease. Thus, prospective studies are urgently needed to confirm the underlying biology, predict patients who are susceptible to HPD, and determine the modality of therapy post progression.

    更新日期:2020-02-07
  • Immune Checkpoint Inhibition in Prostate Cancer
    Trends Cancer (IF 8.884) Pub Date : 2020-02-06
    Lowell Thorndike Nicholson; Lawrence Fong

    Although immunotherapy has proved to be effective in a variety of cancer subtypes, the role of immune checkpoint inhibition in the treatment of prostate cancer remains unclear. Here we review results from the latest clinical trials and discuss data suggesting that certain genetic mutations may confer increased sensitivity to immune checkpoint blockade.

    更新日期:2020-02-07
  • Organoids: A Platform Ready for Glioblastoma Precision Medicine?
    Trends Cancer (IF 8.884) Pub Date : 2020-02-06
    Wei-Lin Jin; Ming-Zhu Jin; Yan-Yang Tu

    Patient-derived organoids can recapitulate parental tumor heterogeneity. In a recent study in Cell, Jacob et al. cultivated glioblastoma organoids (GBOs) to mimic tumor heterogeneity and chimeric antigen receptor (CAR)-T cell immunotherapy, applied it for xenograft establishment and drug testing, and generated a biobank for the timely start of post-operation therapy.

    更新日期:2020-02-07
  • TP53 Mutations and Outcomes in Breast Cancer: Reading beyond the Headlines
    Trends Cancer (IF 8.884) Pub Date : 2020-02-05
    Ashkan Shahbandi; Hoang D. Nguyen; James G. Jackson

    TP53 is the most frequently mutated gene in breast cancer, but its role in survival is confounded by different studies concluding that TP53 mutations are associated with negative, neutral, or positive outcomes. Closer examination showed that many studies were limited by factors such as imprecise methods to detect TP53 mutations and small cohorts that combined patients treated with drugs having very different mechanisms of action. When only studies of patients receiving the same treatment(s) were compared, they tended to agree. These analyses reveal a role for TP53 in response to different treatments as complex as its different biological activities. We discuss studies that have assessed the role of TP53 mutations in breast cancer treatment and limitations in interpreting reported results.

    更新日期:2020-02-06
  • Optical Microscopy and Coherence Tomography of Cancer in Living Subjects
    Trends Cancer (IF 8.884) Pub Date : 2020-02-05
    Peng Si; Alexander Honkala; Adam de la Zerda; Bryan Ronain Smith

    Intravital microscopy (IVM) and optical coherency tomography (OCT) are two powerful optical imaging tools that allow visualization of dynamic biological activities in living subjects with subcellular resolutions. Recent advances in labeling and label-free techniques empower IVM and OCT for a wide range of preclinical and clinical cancer imaging, providing profound insights into the complex physiological, cellular, and molecular behaviors of tumors. Preclinical IVM and OCT have elucidated many otherwise inscrutable aspects of cancer biology, while clinical applications of IVM and OCT are revolutionizing cancer diagnosis and therapies. We review important progress in the fields of IVM and OCT for cancer imaging in living subjects, highlighting key technological developments and their emerging applications in fundamental cancer biology research and clinical oncology investigation.

    更新日期:2020-02-06
  • Glioblastoma Stem Cells: Driving Resilience through Chaos
    Trends Cancer (IF 8.884) Pub Date : 2020-02-03
    Briana C. Prager; Shruti Bhargava; Vaidehi Mahadev; Christopher G. Hubert; Jeremy N. Rich

    Glioblastoma is an aggressive and heterogeneous tumor in which glioblastoma stem cells (GSCs) are at the apex of an entropic hierarchy and impart devastating therapy resistance. The high entropy of GSCs is driven by a permissive epigenetic landscape and a mutational landscape that revokes crucial cellular checkpoints. The GSC population encompasses a complex array of diverse microstates that are defined and maintained by a wide variety of attractors including the complex tumor ecosystem and therapeutic intervention. Constant dynamic transcriptional fluctuations result in a highly adaptable and heterogeneous entity primed for therapy evasion and survival. Analyzing the transcriptional, epigenetic, and metabolic landscapes of GSC dynamics in the context of a stochastically fluctuating tumor network will provide novel strategies to target resistant populations of GSCs in glioblastoma.

    更新日期:2020-02-04
  • Diagnostic Power of DNA Methylation Classifiers for Early Detection of Cancer
    Trends Cancer (IF 8.884) Pub Date : 2020-02-03
    Dhruvajyoti Roy; Maarit Tiirikainen

    DNA methylation-based epigenetic signatures have become valuable cancer biomarkers. We highlight the advantages of liquid biopsy based DNA-methylation profiling for noninvasive diagnosis of early stage cancers and discuss the advanced analytical approaches developed by commercial and academic partnerships.

    更新日期:2020-02-04
  • Premortem Tumor Stress in Radioimmunotherapy
    Trends Cancer (IF 8.884) Pub Date : 2020-01-27
    Ignacio Melero; Maite Alvarez; Luna Minute; Pedro Berraondo

    Recent investigations (Rodriguez-Ruiz et al.) have established the counterintuitive idea that delaying apoptosis upon tumor irradiation by caspase 3 inhibition in tumor cells raises the immunogenicity of dying malignant cells.

    更新日期:2020-01-27
  • Alternative Lengthening of Telomeres: Building Bridges To Connect Chromosome Ends
    Trends Cancer (IF 8.884) Pub Date : 2020-01-23
    Song My Hoang; Roderick J. O’Sullivan

    Alternative lengthening of telomeres (ALT) is a mechanism of telomere maintenance that is observed in many of the most recalcitrant cancer subtypes. Telomeres in ALT cancer cells exhibit a distinctive nucleoprotein architecture shaped by the mismanagement of chromatin that fosters cycles of DNA damage and replicative stress that activate homology-directed repair (HDR). Mutations in specific chromatin-remodeling factors appear to be key determinants of the emergence and survival of ALT cancer cells. However, these may represent vulnerabilities for the targeted elimination of ALT cancer cells that infiltrate tissues and organs to become devastating tumors. In this review we examine recent findings that provide new insights into the factors and mechanisms that mediate telomere length maintenance and survival of ALT cancer cells.

    更新日期:2020-01-24
  • Colorectal Cancer Modeling with Organoids: Discriminating between Oncogenic RAS and BRAF Variants
    Trends Cancer (IF 8.884) Pub Date : 2020-01-21
    Jasmin B. Post; Jeanine M.L. Roodhart; Hugo J.G. Snippert

    RAS and BRAF proteins are frequently mutated in colorectal cancer (CRC) and have been associated with therapy resistance in metastatic CRC patients. RAS isoforms are considered to act as redundant entities in physiological and pathological settings. However, there is compelling evidence that mutant variants of RAS and BRAF have different oncogenic potentials and therapeutic outcomes. In this review we describe similarities and differences between various RAS and BRAF oncogenes in CRC development, histology, and therapy resistance. In addition, we discuss the potential of patient-derived tumor organoids for personalized therapy, as well as CRC modeling using genome editing in preclinical model systems to study similarities and discrepancies between the effects of oncogenic MAPK pathway mutations on tumor growth and drug response.

    更新日期:2020-01-22
  • Trastuzumab Emtansine: Mechanisms of Action and Resistance, Clinical Progress, and Beyond
    Trends Cancer (IF 8.884) Pub Date : 2020-01-21
    Sara García-Alonso; Alberto Ocaña; Atanasio Pandiella

    The approval of ado-trastuzumab emtansine (T-DM1) for clinical use represented a turning point both in HER2-positive breast cancer treatment and antibody–drug conjugate (ADC) technology. T-DM1 has proved its value and effectiveness in advanced metastatic disease as well as in the adjuvant setting. However, its therapeutic potential extends beyond the treatment of breast cancer. Around 100 clinical trials have evaluated or are studying different aspects of T-DM1, such as its role in other HER2 malignancies, rational combinations with immunotherapy, or its function in brain metastasis. Conceptually, many lessons can be learned from this ADC. Understanding its mechanisms of action and the molecular basis underlying resistance to T-DM1 may be relevant to comprehend resistances raised to other ADCs and identify pitfalls that may be overcome.

    更新日期:2020-01-22
  • The Influence of Lung Microbiota on Lung Carcinogenesis, Immunity, and Immunotherapy
    Trends Cancer (IF 8.884) Pub Date : 2020-01-18
    Ariel G. Ramírez-Labrada; Dolores Isla; Angel Artal; Maykel Arias; Antonio Rezusta; Julián Pardo; Eva M. Gálvez

    Microbiota have emerged as key modulators of both the carcinogenic process and the immune response against cancer cells, and, thus, it seems to influence the efficacy of immunotherapy. While most studies have focused on analyzing the influence of gut microbiota, its composition substantially differs from that in the lung. Here, we describe how microbial life in the lungs is associated with host immune status in the lungs and, thus, how the identification of the microbial populations in the lower respiratory tract rather than in the gut might be key to understanding the lung carcinogenic process and to predict the efficacy of different treatments. Understanding the influence of lung microbiota on host immunity may identify new therapeutic targets and help to design new immunotherapy approaches to treat lung cancer.

    更新日期:2020-01-21
  • Targeting the Tumor Microenvironment in Colorectal Peritoneal Metastases
    Trends Cancer (IF 8.884) Pub Date : 2020-01-16
    Wim Ceelen; Robert G. Ramsay; Vignesh Narasimhan; Alexander G. Heriot; Olivier De Wever

    Peritoneal metastasis (PM) occurs in approximately one in four colorectal cancer (CRC) patients. The pathophysiology of colorectal PM remains poorly characterized. Also, the efficacy of current treatment modalities, including surgery and intraperitoneal (IP) delivery of chemotherapy, is limited. Increasingly, therefore, efforts are being developed to unravel the PM cascade and at understanding the PM-associated tumor microenvironment (TME) and peritoneal ecosystem as potential therapeutic targets. Here, we review recent insights in the structure and components of the TME in colorectal PM, and discuss how these may translate into novel therapeutic approaches aimed at re-engineering the metastasis-promoting activity of the stroma.

    更新日期:2020-01-21
  • Targeting the Unfolded Protein Response in Hormone-Regulated Cancers
    Trends Cancer (IF 8.884) Pub Date : 2020-01-16
    Yang Jin; Fahri Saatcioglu

    Cancer cells exploit many of the cellular adaptive responses to support their survival needs. One of these is the unfolded protein response (UPR), a highly conserved signaling pathway that is mounted in response to endoplasmic reticulum (ER) stress. Recent work showed that steroid hormones, in particular estrogens and androgens, regulate the canonical UPR pathways in breast cancer (BCa) and prostate cancer (PCa). In addition, UPR has pleiotropic effects in advanced disease and development of therapy resistance. These findings implicate the UPR pathway as a novel target in hormonally regulated cancers in the clinic. Here, we review the potential therapeutic value of recently developed small molecule inhibitors of UPR in hormone regulated cancers.

    更新日期:2020-01-16
  • Mechanistic Links between Obesity, Insulin, and Cancer
    Trends Cancer (IF 8.884) Pub Date : 2020-01-14
    Rachel J. Perry; Gerald I. Shulman

    Obesity and type 2 diabetes (T2D) increase the prevalence and worsen the prognosis of more than a dozen tumor types; however, the mechanism for this association remains hotly debated. Here we discuss a potential role for insulin as the key hormonal mediator of tumor metabolism and growth in obesity-associated insulin resistance.

    更新日期:2020-01-14
  • Therapeutic Application of PARP Inhibitors in Neuro-Oncology
    Trends Cancer (IF 8.884) Pub Date : 2020-01-13
    Jianfang Ning; Hiroaki Wakimoto

    In response to a variety of cellular stresses, poly(ADP-ribose) polymerase 1 (PARP1) has vital roles in orchestrating DNA damage repair and preserving genomic integrity. Clinical activity of PARP inhibitors (PARPis) in BRCA1/2 mutant cancers validated the concept of synthetic lethality between PARP inhibition and deleterious BRCA1/2 mutations, leading to clinical approval of several PARPis. Preclinical and clinical studies aiming to broaden the therapeutic application of PARPis identified sensitivity biomarkers and rationale combination strategies that can target BRCA wild-type and homologous recombination (HR) DNA repair-proficient cancers, including central nervous system (CNS) malignancies. In this review, we summarize recent progress in PARPi therapy in brain tumors, and discuss current opportunities for, and challenges to, the use of PARPis in neuro-oncology.

    更新日期:2020-01-13
  • Agrin Mediates Angiogenesis in the Tumor Microenvironment
    Trends Cancer (IF 8.884) Pub Date : 2020-01-09
    Sayan Chakraborty; Kizito Njah; Wanjin Hong

    Angiogenesis represents a hallmark of cancer. Several proteoglycans associate with cell surface receptors and regulate angiogenesis within the tumor microenvironment (TME). We highlight the recent discovery that the proteoglycan Agrin cross talks between the tumor and the endothelium to promote an angiogenesis privileged niche during cancer progression.

    更新日期:2020-01-09
  • Tumor Functional Heterogeneity Unraveled by scRNA-seq Technologies
    Trends Cancer (IF 8.884) Pub Date : 2020-01-03
    Laura González-Silva; Laura Quevedo; Ignacio Varela

    Effective cancer treatment has been precluded by the presence of various forms of intratumoral complexity that drive treatment resistance and metastasis. Recent single-cell sequencing technologies are significantly facilitating the characterization of tumor internal architecture during disease progression. New applications and advances occurring at a fast pace predict an imminent broad application of these technologies in many research areas. As occurred with next-generation sequencing (NGS) technologies, once applied to clinical samples across tumor types, single-cell sequencing technologies could trigger an exponential increase in knowledge of the molecular pathways involved in cancer progression and contribute to the improvement of cancer treatment.

    更新日期:2020-01-04
  • Metabolic Fitness and Plasticity in Cancer Progression
    Trends Cancer (IF 8.884) Pub Date : 2020-01-03
    Shawn McGuirk; Yannick Audet-Delage; Julie St-Pierre

    Cancer cells have enhanced metabolic needs due to their rapid proliferation. Moreover, throughout their progression from tumor precursors to metastases, cancer cells face challenging physiological conditions, including hypoxia, low nutrient availability, and exposure to therapeutic drugs. The ability of cancer cells to tailor their metabolic activities to support their energy demand and biosynthetic needs throughout disease progression is key for their survival. Here, we review the metabolic adaptations of cancer cells, from primary tumors to therapy resistant cancers, and the mechanisms underpinning their metabolic plasticity. We also discuss the metabolic coupling that can develop between tumors and the tumor microenvironment. Finally, we consider potential metabolic interventions that could be used in combination with standard therapeutic approaches to improve clinical outcome.

    更新日期:2020-01-04
  • Targeting NAD+ Synthesis to Potentiate CD38-Based Immunotherapy of Multiple Myeloma
    Trends Cancer (IF 8.884) Pub Date : 2019-12-31
    Barry E. Kennedy; Maryanne Sadek; Manal O. Elnenaei; Anthony Reiman; Shashi A. Gujar

    Antibodies targeting CD38, a NAD+-degrading enzyme, have emerged as a promising immunotherapy against multiple myeloma (MM). Currently, the mechanisms by which anti-CD38 antibodies establish their therapeutic effects are poorly understood. Here, we advocate for the depletion of NAD+ to enhance the efficacy of anti-CD38-based immunotherapies in MM.

    更新日期:2019-12-31
  • Immunotherapeutic Transport Oncophysics: Space, Time, and Immune Activation in Cancer
    Trends Cancer (IF 8.884) Pub Date : 2019-12-30
    Sara Nizzero; Haifa Shen; Mauro Ferrari; Bruna Corradetti

    Immuno-oncology has gained momentum thanks to the success of strategies aimed at enhancing immune-mediated antitumor response. The field of immunotherapeutic transport oncophysics investigates the physical processes that drive cancer immunotherapies. This review discusses three main aspects that determine the outcome of an immunotherapy-based treatment from a physical point of view; (i) space, the distribution of cancer and immune cells within tumor masses, (ii) time, the temporal dynamic of immune response against tumors, and (iii) activity, the ability of immune cell populations to suppress cancer. Upon introducing these topics with examples from the literature, we investigate in detail two cases where the interplay between space, time, and activation variables determines immune response: nanodendritic cell vaccines and immunosuppression in ovarian cancer.

    更新日期:2019-12-31
  • Mutant p53 on the Path to Metastasis
    Trends Cancer (IF 8.884) Pub Date : 2019-12-16
    Qiaosi Tang; Zhenyi Su; Wei Gu; Anil K. Rustgi

    Metastasis contributes to the vast majority of cancer-related mortality. Regulatory mechanisms of the multistep invasion-metastasis cascade are being unraveled. TP53 is the most frequently mutated gene across human cancers. Accumulating evidence has shown that mutations of TP53 not only lead to loss of function or dominant negative effects, but also promotes a gain of function. Specifically, gain of function mutant p53 promotes cancer cell motility, invasion, and metastasis. Here, we summarize the mechanisms and functions of mutant p53 that foster metastasis in different types of cancers. We also discuss the prognostic value of mutant p53 and current status of therapeutic strategies targeting mutant p53. Future studies will shed light on discovering novel mechanisms of mutant p53-driven cancer metastasis and developing innovative therapeutics to improve clinical outcomes in patients harboring p53 mutations.

    更新日期:2019-12-17
  • Decoding the Biology of Exosomes in Metastasis
    Trends Cancer (IF 8.884) Pub Date : 2019-12-10
    Bárbara Adem, Patricia F. Vieira, Sonia A. Melo

    Metastasis is the leading cause of cancer mortality. Cancer cells must adapt to colonize and thrive at the metastatic site. The modulation of the receptive organ microenvironment is a key event in the adaptation process and is partially accomplished at a distance by the primary tumor. Exosomes, a subclass of extracellular vesicles (EVs), are distal mediators of communication that carry genetic and molecular information to neighboring and distant cells. Cancer exosomes have been involved in restructuring metastatic sites to support cancer cell colonization. In this article, we discuss the role of exosomes in the metastatic process.

    更新日期:2019-12-11
  • Evolving Significance of Tumor-Normal Sequencing in Cancer Care
    Trends Cancer (IF 8.884) Pub Date : 2019-12-10
    Diana Mandelker, Ozge Ceyhan-Birsoy

    Molecular tests assist at various stages of cancer patient management, including providing diagnosis, predicting prognosis, identifying therapeutic targets, and determining hereditary cancer risk. The current testing paradigm involves germline testing in a subset of patients determined to be at high risk for having a hereditary cancer syndrome, and tumor-only sequencing for treatment decisions in advanced cancer patients. A major limitation of tumor-only sequencing is its inability to distinguish germline versus somatic mutations. Tumor-normal sequencing has emerged as a comprehensive analysis for both hereditary cancer predisposition and somatic profiling. Here, we review recent studies involving tumor-normal sequencing, discuss its benefits in clinical care, challenges for its implementation, and novel insights it has provided regarding tumor biology and germline contribution to cancer.

    更新日期:2019-12-11
  • Does Neuronal Activity Promote Glioma Progression?
    Trends Cancer (IF 8.884) Pub Date : 2019-12-07
    Hans-Georg Wirsching, Michael Weller

    Excessive glutamate release by glioma cells induces pharmacologically accessible neuronal hyperexcitation, including epilepsy. Two recent reports by Venkataramani et al. and Venkatesh et al. suggest that neuronal hyperexcitation stimulates bona fide glutamatergic synapses on glioma cells. Ionotropic glutamate receptors activate intercellular calcium signaling networks to orchestrate glioma cell growth and invasion, presumably by facilitating oncogenic signaling cascades and cytoskeletal remodeling.

    更新日期:2019-12-07
  • Peripheral Circulating CD45RA−FOXP3hi T Regulatory (TReg) II Cells Provide a Window into the Activity of Intratumoral TReg Cells
    Trends Cancer (IF 8.884) Pub Date : 2019-12-03
    Sara I. Pai, Francesco M. Marincola

    The immune landscape of cancer determines its responsiveness to immunotherapy. Tumors infiltrated with CD8+ T cells (immune-active tumors) are more likely to respond to immunomodulatory agents. However, immune activation often is counterbalanced by strong immunosuppressive mechanisms that are necessary to maintain homeostasis but consequentially can facilitate the survival of cancer cells in the immunocompetent host, a concept defined as compensatory immune suppression. TReg cells contribute to compensatory immune suppression, and therapies targeting the immunosuppressive TReg population are being actively explored. Wang et al. characterize a subset of peripheral circulating CD45−FOXP3hi TReg II cells that phenotypically and functionally parallel the activity of their intratumoral counterparts. The findings are paradigm shifting and may provide a potential liquid-based tool to evaluate the immunosuppressive activity of intratumoral TReg cells; they may also allow temporal assessment of whether the fine balance between immune rejection versus tolerance is achieved with various applied therapies.

    更新日期:2019-12-03
  • Regulatory Factor X 7 and its Potential Link to Lymphoid Cancers
    Trends Cancer (IF 8.884) Pub Date : 2019-12-03
    Berenice A. Fischer, Sonia T. Chelbi, Greta Guarda

    Alterations in the Regulatory factor X 7 (RFX7) gene have recurrently been reported in lymphoid cancers. Uncharacterized until recently, this transcription factor regulates genes important for ciliogenesis and for limiting cellular metabolic activity. Here we discuss these observations and conjecture on the links between the reported functions of RFX7 and its potential role in lymphoid cancers, encouraging future studies in these directions.

    更新日期:2019-12-03
  • Tumour Dormancy and Reawakening: Opportunities and Challenges
    Trends Cancer (IF 8.884) Pub Date : 2019-11-25
    Adrienne Boire, Seth B. Coffelt, Sergio A. Quezada, Matthew G. Vander Heiden, Ashani T. Weeraratna

    Tumour dormancy presents challenges for clinical control and opportunities for scientific discovery. Current pictures of the mechanisms of tumour dormancy and reawakening remain incomplete. The Cancer Research UK’s third Marshall Symposium explored tumour dormancy and reawakening in all their forms. In this forum article, we highlight the key challenges and opportunities discussed at this symposium.

    更新日期:2019-11-26
  • The Metabolic Interplay between Cancer and Other Diseases
    Trends Cancer (IF 8.884) Pub Date : 2019-11-21
    Anne Le, Sunag Udupa, Cissy Zhang

    Over the past decade, knowledge of cancer metabolism has expanded exponentially and has provided several clinically relevant targets for cancer therapy. Although these current approaches have shown promise, there are very few studies showing how seemingly unrelated metabolic processes in other diseases can readily occur in cancer. Moreover, the striking metabolic overlap between cancer and other diseases such as diabetes, cardiovascular, neurological, obesity, and aging has provided key therapeutic strategies that have even begun to be translated into clinical trials. These promising results necessitate consideration of the interconnected metabolic network while studying the metabolism of cancer. This review article discusses how cancer metabolism is intertwined with systemic metabolism and how knowledge from other diseases can help to broaden therapeutic opportunities for cancer.

    更新日期:2019-11-21
  • Unmasking the Many Faces of Tumor-Associated Neutrophils and Macrophages: Considerations for Targeting Innate Immune Cells in Cancer
    Trends Cancer (IF 8.884) Pub Date : 2019-11-20
    Tyler Keeley, Diane L. Costanzo-Garvey, Leah M. Cook

    Immunotherapy has emerged at the forefront of cancer therapy; however, patient survival remains low for many cancer types. In consideration of this, non-T cell immune populations, such as innate immune cells, have been identified as potential immunotherapeutic targets. In noncancerous settings, neutrophils are first responders to injury and infection, and work in a partnership with macrophages to regulate inflammation. However, the diversity of tumor-associated neutrophils (TANs) remains elusive. Furthermore, it is likely that TANs and tumor-associated macrophages (TAMs) act in tandem within tumors and contribute both contrasting and synergistic roles in tumor progression. In this Opinion, we discuss the complexity of TAN and TAM functions, the interplay between TANs and TAMs, and major considerations required for implementing TAN/TAM-based therapies.

    更新日期:2019-11-21
  • Migrastatics: Redirecting R&D in Solid Cancer Towards Metastasis?
    Trends Cancer (IF 8.884) Pub Date : 2019-11-16
    Daniel Rosel, Michael Fernandes, Victoria Sanz-Moreno, Jan Brábek

    The concept of 'migrastatics' allows the development of a new drug class that is neither cytotoxic nor antiproliferative but is solely directed towards inhibition of cancer cell motility. Given that the regulatory pathway is open, and migrastatic candidates have been described, it is the right time to enter a new era of antimetastatic treatment.

    更新日期:2019-11-18
  • Multiscale Imaging of Metastasis in Zebrafish
    Trends Cancer (IF 8.884) Pub Date : 2019-11-14
    Naël Osmani, Jacky G. Goetz

    Cancer progression to metastatic dissemination is responsible for ∼90% of deaths in patients. Tremendous efforts have been made to understand primary tumor growth, cancer genetics, and clonal evolution, but also secondary sites of colonization. Intravital imaging technologies are instrumental in understanding key steps of the metastasis cascade, which are believed to be therapeutically relevant targets. However, these remain cumbersome in mouse models. Recent work has demonstrated the zebrafish’s unique ability as an experimental metastasis model for the dynamic study of cancer progression at the single-cell level. Its compatibility with state-of-the art imaging techniques and biophysical approaches allows probing of the interaction of tumor cells with their microenvironment and monitoring of fast and rare cellular events at high spatiotemporal resolution. In this review, we highlight the multiple benefits of the zebrafish as an alternative metastasis preclinical model from an imaging standpoint.

    更新日期:2019-11-14
  • Oncohistone Mutations in Diffuse Intrinsic Pontine Glioma
    Trends Cancer (IF 8.884) Pub Date : 2019-11-09
    Xu Zhang, Zhiguo Zhang

    Diffuse intrinsic pontine glioma (DIPG) is a lethal pediatric tumor with no currently available treatment options. More than 60–70% DIPG tumors harbor heterozygous mutations at genes encoding histone H3 proteins that replace lysine 27 with methionine (K27M). In this review, we discuss how K27M mutation reprograms the cancer epigenome to lead to tumorigenesis, and highlight potential drug targets and therapeutic agents for DIPG.

    更新日期:2019-11-11
  • Immunogenomics of Colorectal Tumors: Facts and Hypotheses on an Evolving Saga
    Trends Cancer (IF 8.884) Pub Date : 2019-11-06
    Irene Catalano, Elena Grassi, Andrea Bertotti, Livio Trusolino

    Immunotherapy with immune checkpoint inhibitors is an approved treatment option for a subpopulation of patients with colorectal cancers that display microsatellite instability. However, not all individuals within this subgroup respond to immunotherapy, and molecular biomarkers for effective patient stratification are still lacking. In this opinion article, we provide an overview of the different biological parameters that contribute to rendering colorectal cancers with microsatellite instability potentially sensitive to immunotherapy. We critically discuss the reasons why such parameters have limited predictive value and the implications therein. We also consider that a more informed knowledge of response determinants in this tumor subtype could help understand the mechanisms of immunotherapy resistance in microsatellite stable tumors. We conclude that the dynamic nature of the interactions between cancer and immune cells complicates conventional biomarker development and argue that a new generation of adaptive metrics, borrowed from evolutionary genetics, may improve the effectiveness and reliability of clinical decision making.

    更新日期:2019-11-07
  • Metabolic Regulation of Macrophage Polarization in Cancer
    Trends Cancer (IF 8.884) Pub Date : 2019-11-06
    Kamiya Mehla, Pankaj K. Singh

    Macrophages act as scavengers, modulating the immune response against pathogens and maintaining tissue homeostasis. Metabolism governs macrophage differentiation, polarization, mobilization, and the ability to mount an effective antitumor response. However, in cancer, the tumor microenvironment (TME) can actively reprogram macrophage metabolism either by direct exchange of metabolites or through cytokines and other signaling mediators. Thus, metabolic reprogramming holds potential for modulating macrophages and developing new therapeutic approaches. In this review, we provide an overview of macrophage metabolism as it relates to macrophage function and plasticity in cancer.

    更新日期:2019-11-06
  • Cannibalism in Breast Cancer: The Dangers of Overeating
    Trends Cancer (IF 8.884) Pub Date : 2019-11-06
    Sue Haupt, Simon P. Keam, Ygal Haupt

    Cancer cells devouring their neighbours to survive drug treatment is an abhorrent concept. Yet it holds hope for exploring new anticancer treatments. Tonnessen-Murray et al. adopted elegant cell-labelling methods using real-time microscopy to observe ‘cellular gorging’ by drug-treated cells. They discovered that in response to drug treatment, cells that became ‘cannibals’ were able to outlive their unindulged neighbours.

    更新日期:2019-11-06
  • Metronomic Maintenance Therapy for Rhabdomyosarcoma
    Trends Cancer (IF 8.884) Pub Date : 2019-11-04
    Nicolas André, Nadège Corradini, Yuval Shaked

    In a recent article, Bisogno et al. reported in a randomized trial that addition of metronomic maintenance therapy (MMT) with vinorelbine plus cyclophosphamide for children with rhabdomyosarcoma resulted in a significant increase in overall and event-free survival. Although the mechanism of action remains to be fully elucidated, this study paves the way for further evaluation of MMT as a potential therapeutic strategy in pediatric patients with high-risk disease.

    更新日期:2019-11-05
  • Harnessing the Microbiome for Pancreatic Cancer Immunotherapy
    Trends Cancer (IF 8.884) Pub Date : 2019-11-04
    Gerardo A. Vitiello, Deirdre J. Cohen, George Miller

    Late-stage pancreatic cancer harbors a fibrotic and immune-excluded tumor microenvironment that impedes immunotherapy success. A key to unlocking pancreatic cancer immunotherapy may be treating early-stage pancreatic cancer, when peripancreatic inflammation promoted by the microbiome potentiates oncogenic signaling and suppresses innate and adaptive immunity. Hence, understanding the role of microbiota in pancreatic cancer initiation, progression, and immunosuppression is crucial. We propose that not only are microbiota targets for immunomodulation in this disease, but also that microbiome profiling has a potential role in pancreatic cancer screening. Furthermore, combining microbiome profiling with liquid and tissue biopsy may validate the early pancreatic cancer treatment approach of microbiome modulation and immunotherapy.

    更新日期:2019-11-05
  • Lipid Metabolism at the Nexus of Diet and Tumor Microenvironment
    Trends Cancer (IF 8.884) Pub Date : 2019-10-31
    Barrie Peck, Almut Schulze

    Obesity is a leading contributing factor to cancer development worldwide. Epidemiological evidence suggests that diet affects cancer risk and also substantially alters therapeutic outcome. Therefore, studying the impact of diet in the development and treatment of cancer should be a clinical priority. In this Review, we set out the evidence supporting the role of lipid metabolism in shaping the tumor microenvironment (TME) and cancer cell phenotype. We will discuss how dietary lipids can impact phenotype thereby affecting disease trajectory and treatment response. Finally, we will posit potential strategies on how this knowledge can be exploited to increase treatment efficacy and patient survival.

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Surviving at a Distance: Organ-Specific Metastasis.
    Trends Cancer (IF 8.884) Pub Date : 2015-09-01
    Anna C Obenauf,Joan Massagué

    The clinical manifestation of metastasis in a vital organ is the final stage of cancer progression and the main culprit of cancer-related mortality. Once established, metastasis is devastating, but only a small proportion of the cancer cells that leave a tumor succeed at infiltrating, surviving, and ultimately overtaking a distant organ. The bottlenecks that challenge cancer cells in newly invaded microenvironments are organ-specific and consequently demand distinct mechanisms for metastatic colonization. We review the metastatic traits that allow cancer cells to colonize distinct organ sites.

    更新日期:2019-11-01
  • Hypoxia: Signaling the Metastatic Cascade.
    Trends Cancer (IF 8.884) Pub Date : 2017-07-26
    Erinn B Rankin,Jin-Min Nam,Amato J Giaccia

    Hypoxia is a potent microenvironmental factor that promotes tumor metastasis. Recent studies have revealed mechanisms by which hypoxia and activation of hypoxia inducible factor (HIF)-dependent signaling promotes metastasis through the regulation of metabolic reprogramming, the stem cell phenotype, invasion, angiogenesis, immune suppression, the premetastatic niche, intravasation and/or extravasation, and resistance to apoptosis. These discoveries suggest novel paradigms in tumor metastasis and identify new opportunities for therapeutic intervention in the prevention and treatment of metastatic disease. Here, we review the impact of hypoxia and hypoxic signaling pathways in tumor and stromal cells on each step of the metastatic cascade.

    更新日期:2019-11-01
  • The 'Pushmi-Pullyu' of DNA REPAIR: Clinical Synthetic Lethality.
    Trends Cancer (IF 8.884) Pub Date : 2017-07-26
    S Percy Ivy,Johann de Bono,Elise C Kohn

    Maintenance of genomic integrity is critical for adaptive survival in the face of endogenous and exogenous environmental stress. The loss of stability and fidelity in the genome caused by cancer and cancer treatment provides therapeutic opportunities to leverage the critical balance between DNA injury and repair. Blocking repair and pushing damaged DNA through the cell cycle using therapeutic inhibitors exemplify the 'pushmi-pullyu' effect of disrupted DNA repair. DNA repair inhibitors (DNARi) can be separated into five biofunctional categories: sensors, mediators, transducers, effectors, and collaborators that recognize DNA damage, propagate injury DNA messages, regulate cell cycle checkpoints, and alter the microenvironment. The result is cancer therapeutics that takes advantage of clinical synthetic lethality, resulting in selective tumor cell kill. Here, we review recent considerations related to DNA repair and new DNARi agents and organize those findings to address future directions and clinical opportunities.

    更新日期:2019-11-01
  • CRISPR/Cas9: From Genome Engineering to Cancer Drug Discovery.
    Trends Cancer (IF 8.884) Pub Date : 2017-06-13
    Ji Luo

    Advances in translational research are often driven by new technologies. The advent of microarrays, next-generation sequencing, proteomics and RNA interference (RNAi) have led to breakthroughs in our understanding of the mechanisms of cancer and the discovery of new cancer drug targets. The discovery of the bacterial clustered regularly interspaced palindromic repeat (CRISPR) system and its subsequent adaptation as a tool for mammalian genome engineering has opened up new avenues for functional genomics studies. This review will focus on the utility of CRISPR in the context of cancer drug target discovery.

    更新日期:2019-11-01
  • DNA-Targeted Precision Medicine; Have we Been Caught Sleeping?
    Trends Cancer (IF 8.884) Pub Date : 2017-06-13
    William C Reinhold,Anish Thomas,Yves Pommier

    In the current drive to incorporate molecular markers into treatment-selection for precision medicine, there has been a significant and we believe ill-advised omission of the large and routinely used group of drugs whose mechanism of action is DNA damage.

    更新日期:2019-11-01
  • Calmodulin and PI3K Signaling in KRAS Cancers.
    Trends Cancer (IF 8.884) Pub Date : 2017-05-04
    Ruth Nussinov,Guanqiao Wang,Chung-Jung Tsai,Hyunbum Jang,Shaoyong Lu,Avik Banerjee,Jian Zhang,Vadim Gaponenko

    Calmodulin (CaM) uniquely promotes signaling of oncogenic K-Ras; but not N-Ras or H-Ras. How CaM interacts with K-Ras and how this stimulates cell proliferation are among the most challenging questions in KRAS-driven cancers. Earlier data pointed to formation of a ternary complex consisting of K-Ras, PI3Kα and CaM. Recent data point to phosphorylated CaM binding to the SH2 domains of the p85 subunit of PI3Kα and activating it. Modeling suggests that the high affinity interaction between the phosphorylated CaM tyrosine motif and PI3Kα, can promote full PI3Kα activation by oncogenic K-Ras. Our up-to-date review discusses CaM's role in PI3K signaling at the membrane in KRAS-driven cancers. This is significant since it may help development of K-Ras-specific pharmacology.

    更新日期:2019-11-01
  • Cancer Prevention: Lessons Learned and Future Directions.
    Trends Cancer (IF 8.884) Pub Date : 2017-02-01
    Barbara K Dunn,Barnett S Kramer

    In this review, we address selected areas that are central to the state-of-the-art of cancer prevention science. The emphasis on prevention as a viable and critical approach to decreasing cancer mortality has gained traction in recent years, evidenced by its inclusion in the US Vice President's Cancer Initiative (also termed 'Moonshot'). Cancer prevention occurs by arresting, slowing down, or reversing the carcinogenic process before invasion into surrounding tissue or by avoiding or blocking causative exposure. An important challenge is to identify individuals who will benefit most from preventive interventions with the least possible harm. Preventive interventions range from avoiding known carcinogens (e.g., tobacco or asbestos) to intervening with anticarcinogenic strategies (behavioral modifications , such as diet and exercise; medications; nutritional agents; and vaccination against causative agents). Here, we focus on active intervention with measures involving pharmaceutical and immunological agents.

    更新日期:2019-11-01
  • Screening for Cancer in Persons Living with HIV Infection.
    Trends Cancer (IF 8.884) Pub Date : 2016-11-29
    James J Goedert,H Dean Hosgood,Robert J Biggar,Howard D Strickler,Charles S Rabkin

    Survival with human immunodeficiency virus (HIV) infection has greatly improved due to effective antiretroviral therapy (ART). As infectious complications have declined, malignancy now accounts for over one-third of deaths among people living with HIV (PLWH). Based on practices in the general population, cancer screening of PLWH can decrease both morbidity and mortality. In this article, we review and consider directed approaches for colorectal, breast, cervical and lung cancer screening. Furthermore, routine physical examinations may detect lymphomas and skin, anal and oral cancers. Comprehensive cancer prevention in PLWH should also include ART adherence, vaccination against oncogenic viruses, treatment of hepatitis viruses and smoking cessation. Cancer screening for PLWH warrants further research on safety and efficacy as well as targeted efforts to increase adherence.

    更新日期:2019-11-01
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