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  • 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
  • Radiotherapy: Changing the Game in Immunotherapy.
    Trends Cancer (IF 8.884) Pub Date : 2016-10-25
    Sandra Demaria,C Norman Coleman,Silvia C Formenti

    Immune checkpoint inhibitors are effective in cancer treatment. A pre-existing immune response demonstrated by significant pretreatment tumor lymphocytic infiltration is a pre-requisite for response. Within such infiltrated tumors, referred as "hot", immune checkpoint inhibitors rescue anti-tumor T cells activity. In contrast, "cold" tumors lack lymphocytic infiltration and are refractory to immunotherapy. Preclinical data show that radiotherapy sensitizes refractory tumors to immune checkpoint inhibitors by recruiting anti-tumor T cells. Despite the growing number of clinical studies testing radiation's ability to enhance immunotherapy, clinical evidence that it converts cold tumors into responsive ones remains elusive. Here we review evidence that radiotherapy is not only an occasional enhancer of immunotherapy's effects but a "game changer", and propose a blueprint to test this.

    更新日期:2019-11-01
  • The journey of DNA repair.
    Trends Cancer (IF 8.884) Pub Date : 2016-02-10
    Natalie Saini

    21 years ago, the DNA Repair Enzyme was declared "Molecule of the Year". Today, we are celebrating another "year of repair", with the 2015 Nobel Prize in Chemistry being awarded to Aziz Sancar, Tomas Lindahl and Paul Modrich for their collective work on the different DNA repair pathways.

    更新日期:2019-11-01
  • Mutations, Cancer and the Telomere Length Paradox.
    Trends Cancer (IF 8.884) Pub Date : 2017-07-19
    Abraham Aviv,James J Anderson,Jerry W Shay

    Individuals with short telomeres should be at increased risk for cancer, since short telomeres lead to genomic instability - a hallmark of cancer. However, individuals with long telomeres also display an increased risk for major cancers, thus creating a cancer-telomere length (TL) paradox. The two-stage clonal expansion model we propose is based on the thesis that a series of mutational hits (1st Hit) at the stem-cell level generates a clone with replicative advantage. A series of additional mutational hits (2nd Hit) transforms the expanding clone into cancer. By proposing that the 1st Hit is largely telomere length-independent, while the 2nd Hit is largely TL-dependent, we resolve the paradox, highlighting a regulatory role of telomeres in cancer.

    更新日期:2019-11-01
  • Gluconeogenesis of Cancer Cells Is Disrupted by Citrate.
    Trends Cancer (IF 8.884) Pub Date : 2019-06-09
    Philippe Icard,Zherui Wu,Marco Alifano,Ludovic Fournel

    更新日期:2019-11-01
  • Cancer as a Matter of Fat: The Crosstalk between Adipose Tissue and Tumors.
    Trends Cancer (IF 8.884) Pub Date : 2018-05-02
    Ernst Lengyel,Liza Makowski,John DiGiovanni,Mikhail G Kolonin

    Obesity has been linked to the increased risk and aggressiveness of many types of carcinoma. A state of chronic inflammation in adipose tissue (AT), resulting in genotoxic stress, may contribute to carcinogenesis and cancer initiation. Evidence that AT plays a role in cancer aggressiveness is solid and mounting. During cancer progression, tumor cells engage in a metabolic symbiosis with adjacent AT. Mature adipocytes provide adipokines and lipids to cancer cells, while stromal and immune cells from AT infiltrate carcinomas and locally secrete paracrine factors within the tumor microenvironment. This review focuses on the crosstalk between AT and tumor cells that promotes tumor growth and increases cellular lipid metabolism, metastasis, and chemoresistance.

    更新日期:2019-11-01
  • New Therapies in Head and Neck Cancer.
    Trends Cancer (IF 8.884) Pub Date : 2018-05-02
    Rodell T Santuray,Daniel E Johnson,Jennifer R Grandis

    Head and neck squamous cell carcinoma (HNSCC) is a common malignancy with high rates of mortality and morbidity. Beginning with cetuximab, investigators continue to optimize antibody technology to target cell-surface receptors that promote HNSCC growth. Small molecules and oligonucleotides have also emerged as therapeutic inhibitors of key receptor-mediated signaling pathways. Although many such therapies have been disappointing in clinical trials as single agents, they continue to be studied in combination with standard therapies. Approvals of pembrolizumab and nivolumab opened a new era of immunotherapy that aims to stimulate antitumor immunity in the tumor microenvironment. Immunotherapies are being intensively investigated in new HNSCC clinical trials, with the goal of optimizing the therapeutic potential of this new class of anticancer agent.

    更新日期:2019-11-01
  • Noninvasive PET Imaging of T cells.
    Trends Cancer (IF 8.884) Pub Date : 2018-05-02
    Weijun Wei,Dawei Jiang,Emily B Ehlerding,Quanyong Luo,Weibo Cai

    The rapidly evolving field of cancer immunotherapy recently saw the approval of several new therapeutic antibodies. Several cell therapies, for example, chimeric antigen receptor-expressing T cells (CAR-T), are currently in clinical trials for a variety of cancers and other diseases. However, approaches to monitor changes in the immune status of tumors or to predict therapeutic responses are limited. Monitoring lymphocytes from whole blood or biopsies does not provide dynamic and spatial information about T cells in heterogeneous tumors. Positron emission tomography (PET) imaging using probes specific for T cells can noninvasively monitor systemic and intratumoral immune alterations during experimental therapies and may have an important and expanding value in the clinic.

    更新日期:2019-11-01
  • Molecular Discriminators of Racial Disparities in Prostate Cancer.
    Trends Cancer (IF 8.884) Pub Date : 2016-03-01
    Bushra Ateeq,Vipul Bhatia,Sakshi Goel

    Recent molecular characterization of prostate cancer (PCa) identified novel genetic aberrations and disease subtypes. The frequencies of molecular aberrations show racial disparity. Clinical strategies and targeted therapies embracing these racial differences are required. Here we discuss ethnic differences in genetic alterations and their impact on the susceptibility, progression, and treatment of prostate cancer.

    更新日期:2019-11-01
  • Mitotic DNA Damage Response: At the Crossroads of Structural and Numerical Cancer Chromosome Instabilities.
    Trends Cancer (IF 8.884) Pub Date : 2017-07-19
    Samuel F Bakhoum,Lilian Kabeche,Duane A Compton,Simon N Powell,Holger Bastians

    DNA double-strand breaks (DSBs) prevent cells from entering mitosis allowing cells to repair their genomic damage. Little is known about the response to DSBs once cells have already committed to mitosis. Here, we review the genome-protective role of the mitotic DNA damage response (DDR) and evidence suggesting that its untimely activation induces chromosome segregation errors and paradoxically undermines genomic integrity. In contrast to normal cells, cancer cells coopt this pathway to propagate structural and numerical chromosomal instabilities. Cells derived from genomically unstable tumors exhibit evidence for a partially activated DDR during mitosis, which leads to ongoing chromosome segregation errors. Thus, a thorough understanding of the consequences of mitotic DNA damage is key to our ability to devise novel anticancer therapeutic strategies.

    更新日期:2019-11-01
  • The Hidden Conundrum of Phosphoinositide Signaling in Cancer.
    Trends Cancer (IF 8.884) Pub Date : 2016-11-08
    Narendra Thapa,Xiaojun Tan,Suyong Choi,Paul F Lambert,Alan C Rapraeger,Richard A Anderson

    Phosphoinositide 3-kinase (PI3K) generation of PI(3,4,5)P3 from PI(4,5)P2 and the subsequent activation of Akt and its downstream signaling cascades (e.g. mTORC1) dominates the landscape of phosphoinositide signaling axis in cancer research. However, PI(4,5)P2 is breaking its boundary as merely a substrate for PI3K and phospholipase C (PLC), and is now an established lipid messenger pivotal for different cellular events in cancer. Here, we review the phosphoinositide signaling axis in cancer, giving due weight to PI(4,5)P2 and its generating enzymes, the phosphatidylinositol phosphate (PIP) kinases (PIPKs). We highlighted how PI(4,5)P2 and PIP kinases serve as a proximal node in phosphoinositide signaling axis and how its interaction with cytoskeletal proteins regulates migratory and invasive nexus of metastasizing tumor cells.

    更新日期:2019-11-01
  • Squamous Transition of Lung Adenocarcinoma and Drug Resistance.
    Trends Cancer (IF 8.884) Pub Date : 2017-07-26
    Shenda Hou,Xiangkun Han,Hongbin Ji

    Studies in mouse models support an essential role of lung adenocarcinoma (ADC) to squamous cell carcinoma (SCC) transition (AST) in the development of drug resistance. Recent observations in the clinic further suggest that this type of histological transition may be responsible for resistance to tyrosine kinase inhibitor (TKI) therapy and chemotherapy in relapsed EGFR-mutant lung ADC patients. Here we summarize the current understanding of AST and drug resistance.

    更新日期:2019-11-01
  • Development versus Evolution in Cancer Biology.
    Trends Cancer (IF 8.884) Pub Date : 2018-05-02
    Fabio Marongiu,Monica Serra,Ezio Laconi

    The terms 'development' and 'evolution' are both used to describe the unfolding of the carcinogenic process. However, there is increasing awareness of an essential difference in the meanings of these two terms with reference to cancer. We discuss evidence suggesting that the concepts of development and evolution are both pertinent to the description of carcinogenesis; however, they appropriately apply to distinct phases of a multistep process. Such a distinction bears important implications for the study and management of cancer.

    更新日期:2019-11-01
  • Actionable molecular biomarkers in primary brain tumors.
    Trends Cancer (IF 8.884) Pub Date : 2017-06-13
    Verena Staedtke,Omar Dildar a Dzaye,Matthias Holdhoff

    Recent genome-wide studies of malignancies of the central nervous system (CNS) have revolutionized our understanding of the biology of these tumors. This newly gained knowledge provides a wealth of opportunity for biomarker driven clinical research. To date, however, only few of the available molecular markers truly influence clinical decision-making and treatment. The most widely validated markers in neuro-oncology presently are: 1) MGMT promoter methylation as a prognostic and predictive marker in glioblastoma, 2) co-deletion of 1p and 19q differentiating oligodendrogliomas from astrocytomas, 3) IDH1/2 mutations, and 4) select pathway-associated mutations. This article focuses on currently impactful biomarkers in adult and pediatric brain cancers and it provides a perspective on the direction of research in this field.

    更新日期:2019-11-01
  • A Physical View of Cancer.
    Trends Cancer (IF 8.884) Pub Date : 2018-04-03
    Rakesh K Jain,Ana Batista

    更新日期:2019-11-01
  • The evolution of lifespan and age-dependent cancer risk.
    Trends Cancer (IF 8.884) Pub Date : 2017-04-26
    Andrii I Rozhok,James DeGregori

    The Armitage-Doll multi-stage model of carcinogenesis tremendously refocused cancer science by postulating that carcinogenesis is driven by a sequence of genetic changes in cells. Age-dependent cancer incidence thus has been explained in terms of the time necessary for oncogenic mutations to occur. While the multi-step nature of cancer evolution is well-supported by evidence, the mutation-centric theory is unable to explain a number of phenomena, such as the disproportion between cancer frequency and animal body size or the scaling of cancer incidence to animal lifespan. In this paper, we present a theoretical review of the current paradigm and discuss some fundamental evolutionary theory postulates that explain why cancer incidence is a function of lifespan and physiological, not chronological, aging.

    更新日期:2019-11-01
  • Modeling Tumor Clonal Evolution for Drug Combinations Design.
    Trends Cancer (IF 8.884) Pub Date : 2017-04-25
    Boyang Zhao,Michael T Hemann,Douglas A Lauffenburger

    Cancer is a clonal evolutionary process. This presents challenges for effective therapeutic intervention, given the constant selective pressure towards drug resistance. Mathematical modeling from population genetics, evolutionary dynamics, and engineering perspectives are being increasingly employed to study tumor progression, intratumoral heterogeneity, drug resistance, and rational drug scheduling and combinations design. In this review, we discuss promising opportunities these inter-disciplinary approaches hold for advances in cancer biology and treatment. We propose that quantitative modeling perspectives can complement emerging experimental technologies to facilitate enhanced understanding of disease progression and improved capabilities for therapeutic drug regimen designs.

    更新日期:2019-11-01
  • Glutamine Metabolism in Cancer: Understanding the Heterogeneity.
    Trends Cancer (IF 8.884) Pub Date : 2017-04-11
    Ahmad A Cluntun,Michael J Lukey,Richard A Cerione,Jason W Locasale

    Reliance on glutamine has long been considered a hallmark of cancer cell metabolism. However, some recent studies have challenged this notion in vivo, prompting a need for further clarifications on the role of glutamine metabolism in cancer. We find that there is ample evidence of an essential role for glutamine in tumors and that a variety of factors, including tissue type, the underlying cancer genetics, the tumor microenvironment and other variables such as diet and host physiology collectively influence the role of glutamine in cancer. Thus the requirements for glutamine in cancer are overall highly heterogeneous. In this review, we discuss the implications both for basic science and for targeting glutamine metabolism in cancer therapy.

    更新日期:2019-11-01
  • The Heterocellular Emergence of Colorectal Cancer.
    Trends Cancer (IF 8.884) Pub Date : 2017-02-28
    Christopher J Tape

    Tissues contain multiple different cell types and can be considered to be heterocellular systems. Signaling between different cells allows tissues to achieve phenotypes that no cell type can achieve in isolation. Such emergent tissue-level phenotypes can be said to 'supervene upon' heterocellular signaling. It is proposed here that cancer is also an emergent phenotype that supervenes upon heterocellular signaling. Using colorectal cancer (CRC) as an example, I review how heterotypic cells differentially communicate to support emergent malignancy. Studying tumors as integrated heterocellular systems - rather than as solitary expansions of mutated cells - may reveal novel ways to treat cancer.

    更新日期:2019-11-01
  • The Strange Case of CDK4/6 Inhibitors: Mechanisms, Resistance, and Combination Strategies.
    Trends Cancer (IF 8.884) Pub Date : 2017-03-18
    Erik S Knudsen,Agnieszka K Witkiewicz

    CDK4/6 inhibitors have emerged as a powerful class of agents with clinical activity in a number of malignancies. Targeting the cell cycle represents a core attack on a defining feature of cancer. However, the mechanisms through which selective CDK4/6 targeted agents act has few parallels in the current pharmaceutical armamentarium against cancer. Notably, CDK4/6 inhibitors act downstream of most mitogenic signaling cascades, which have implications both related to clinical efficacy and resistance. Core knowledge of cell cycle processes has provided insights into mechanisms of intrinsic resistance to CDK4/6 inhibitors; however, the basis of acquired resistance versus durable response is only beginning to emerge. This review focuses on the mechanism of action and biomarkers to direct the precision use of CDK4/6 inhibitors and rationally-developed combination therapies.

    更新日期:2019-11-01
  • RP-MDM2-p53 Pathway: Linking Ribosomal Biogenesis and Tumor Surveillance.
    Trends Cancer (IF 8.884) Pub Date : 2016-04-01
    Yong Liu,Chad Deisenroth,Yanping Zhang

    Ribosomal biogenesis is tightly associated with cellular activities, such as growth, proliferation, and cell cycle progression. Perturbations in ribosomal biogenesis can initiate so-called nucleolar stress. The process through which ribosomal proteins (RPs) transduce nucleolar stress signals via MDM2 to p53 has been described as a crucial tumor-suppression mechanism. In this review we focus on recent progress pertaining to the function and mechanism of RPs in association with the MDM2-p53 tumor-suppression network, and the potential implications this surveillance network has for cancer development.

    更新日期:2019-11-01
  • Intravital Insights into Heterogeneity, Metastasis, and Therapy Responses.
    Trends Cancer (IF 8.884) Pub Date : 2016-04-01
    Colinda L G J Scheele,Carrie Maynard,Jacco van Rheenen

    Tumor progression is driven by a series of genetic and microenvironmental changes. These events lead to heterogeneous tumors which consist of a variety of cells from which some cells may possess properties which promote survival after therapy and metastasis. Recent advances in intravital microscopy (IVM) have enabled visualization of this tumor heterogeneity over time at a single-cell resolution. We highlight here the latest IVM studies that have revealed the dynamic interactions between the tumor cells and their local microenvironment. We review the most recent data that exposes how these dynamic interactions cause an additional increase in tumor heterogeneity, resulting in multiple metastatic strategies and facilitating therapy resistance.

    更新日期:2019-11-01
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