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- Volume 1, 2017
Annual Review of Cancer Biology - Volume 1, 2017
Volume 1, 2017
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How Tumor Virology Evolved into Cancer Biology and Transformed Oncology
Vol. 1 (2017), pp. 1–18More LessThe field of cancer biology has recently come of age, as witnessed by the initiation of this Annual Reviews journal this year. In this article, I argue that the major sources of cancer biology reside neither in cell biology nor in traditional cancer research, but instead in the domain once called “tumor virology.” Speaking from the perspective of someone who “rode the wave” that uncovered cancer genes and their effects on cell behavior, I have tried to trace the influences, discoveries, and changing attitudes and practices that produced the vibrant scientific landscape that we now enjoy.
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The Role of Autophagy in Cancer
Vol. 1 (2017), pp. 19–39More LessAutophagy is a highly conserved and regulated process that targets proteins and damaged organelles for lysosomal degradation to maintain cell metabolism, genomic integrity, and cell survival. The role of autophagy in cancer is dynamic and depends, in part, on tumor type and stage. Although autophagy constrains tumor initiation in normal tissue, some tumors rely on autophagy for tumor promotion and maintenance. Studies in genetically engineered mouse models support the idea that autophagy can constrain tumor initiation by regulating DNA damage and oxidative stress. In established tumors, autophagy can also be required for tumor maintenance, allowing tumors to survive environmental stress and providing intermediates for cell metabolism. Autophagy can also be induced in response to chemotherapeutics, acting as a drug-resistance mechanism. Therefore, targeting autophagy is an attractive cancer therapeutic option currently undergoing validation in clinical trials.
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Cell Cycle–Targeted Cancer Therapies
Vol. 1 (2017), pp. 41–57More LessA cardinal feature of cancer cells is the deregulation of cell cycle controls. Targeted drug therapy is designed to take advantage of specific genetic alterations that distinguish tumor cells from their normal counterparts. Mutated oncogenes and inactivated tumor suppressors can increase the dependency of cancer cells on G1-phase cyclin-dependent kinases, augment replication stress and DNA damage during S phase, and dismantle checkpoints that monitor progression through S/G2/M. These acquired defects generate cancer cell–specific vulnerabilities that provide a window of opportunity for targeted cancer treatments. We review the basic principles underlying the design of targeted therapies with emphasis on two main features: oncogene addiction and synthetic lethality. We discuss how traditional cytotoxic agents may depend, with relatively less specificity, on these same features and then point to examples of the successful application of newly developed, targeted therapeutic agents that offer reduced, dose-limiting toxicities to normal cells.
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Ubiquitin in Cell-Cycle Regulation and Dysregulation in Cancer
Vol. 1 (2017), pp. 59–77More LessUncontrolled cell proliferation and genomic instability are common features of cancer and can arise from, respectively, the loss of cell-cycle control and defective checkpoints. Ubiquitin-mediated proteolysis, ultimately executed by ubiquitin-ligating enzymes (E3s), plays a key part in cell-cycle regulation and is dominated by two multisubunit E3s, the anaphase-promoting complex (or cyclosome) (APC/C) and SKP1–cullin-1–F-box (SCF) complex. We highlight the role of APC/C and the SCF bound to F-box proteins, FBXW7, SKP2, and β-TrCP, in regulating the abundance of select fundamental proteins, primarily during the cell cycle, that are associated with human cancer. The clinical success of the first proteasome inhibitor, bortezomib, in treating multiple myeloma and mantle-cell lymphoma set the precedent for viewing the ubiquitin–proteasome system as a druggable target for cancer. Given that there are more E3s than kinases, selective, small-molecule E3 inhibitors have the potential of opening up another dimension in the therapeutic armamentarium for the treatment of cancer.
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The Two Faces of Reactive Oxygen Species in Cancer
Vol. 1 (2017), pp. 79–98More LessReactive oxygen species (ROS), now appreciated for their cellular signaling capabilities, have a dual role in cancer. On the one hand, ROS can promote protumorigenic signaling, facilitating cancer cell proliferation, survival, and adaptation to hypoxia. On the other hand, ROS can promote antitumorigenic signaling and trigger oxidative stress–induced cancer cell death. To hyperactivate the cell signaling pathways necessary for cellular transformation and tumorigenesis, cancer cells increase their rate of ROS production compared with normal cells. Concomitantly, in order to maintain ROS homeostasis and evade cell death, cancer cells increase their antioxidant capacity. Compared with normal cells, this altered redox environment of cancer cells may increase their susceptibility to ROS-manipulation therapies. In this review, we discuss the two faces of ROS in cancer, the potential mechanisms underlying ROS signaling, and the opposing cancer therapeutic approaches to targeting ROS.
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Analyzing Tumor Metabolism In Vivo
Vol. 1 (2017), pp. 99–117More LessAltered metabolism is a clinically actionable hallmark of cancer. Some reprogrammed activities in cancer cells have predictive value and others are associated with therapeutic liabilities. Recent years have brought increased exploration of metabolism in intact tumors, complementing a large literature on cancer cell lines. We review the expanding tool kit available for studying the metabolic features of tumors in vivo. These techniques include metabolomics, positron emission tomography, magnetic resonance spectroscopy, and multiparametric magnetic resonance imaging, and they vary according to their invasiveness and breadth of metabolic assessment. Special attention is given to the emerging role of intraoperative infusions of stable, isotope-labeled nutrients, which have provided the first view of true metabolic flux in human tumors. These studies also demonstrate markedly different metabolic phenotypes from those observed in culture, indicating the potential for this approach to provide a disease-relevant view of cancer metabolism and to nominate new therapeutic targets from reprogrammed pathways.
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Stress-Induced Mutagenesis: Implications in Cancer and Drug Resistance
Vol. 1 (2017), pp. 119–140More LessGenomic instability underlies many cancers and generates genetic variation that drives cancer initiation, progression, and therapy resistance. In contrast with classical assumptions that mutations occur purely stochastically at constant, gradual rates, microbes, plants, flies, and human cancer cells possess mechanisms of mutagenesis that are upregulated by stress responses. These generate transient, genetic-diversity bursts that can propel evolution, specifically when cells are poorly adapted to their environments—that is, when stressed. We review molecular mechanisms of stress-response-dependent (stress-induced) mutagenesis that occur from bacteria to cancer, and are activated by starvation, drugs, hypoxia, and other stressors. We discuss mutagenic DNA break repair in Escherichia coli as a model for mechanisms in cancers. The temporal regulation of mutagenesis by stress responses and spatial restriction in genomes are common themes across the tree of life. Both can accelerate evolution, including the evolution of cancers. We discuss possible anti-evolvability drugs, aimed at targeting mutagenesis and other variation generators, that could be used to delay the evolution of cancer progression and therapy resistance.
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Synthetic Lethality in Cancer Therapeutics
Vol. 1 (2017), pp. 141–161More LessTreatment with targeted drugs has primarily focused on the genes and pathways that are mutated in cancer, which severely limits the repertoire of drug targets. Synthetic lethality exploits the notion that the presence of a mutation in a cancer gene is often associated with a new vulnerability that can be targeted therapeutically, thus greatly expanding the arsenal of potential drug targets. Here we discuss both the experimental and the computational biology tools that can be used to identify synthetic lethal interactions. We also discuss strategies for using synthetic lethality to discover new drug targets and in the rational design of more potent drug combinations. We review the progress made and future opportunities offered by synthetic lethal approaches to treating cancer more effectively.
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Noncoding RNAs in Cancer Development
Chao-Po Lin, and Lin HeVol. 1 (2017), pp. 163–184More LessIt is becoming increasingly clear that a large repertoire of noncoding RNAs (ncRNAs) are actively transcribed from the mammalian genome, regulating diverse cellular processes in development and diseases through a variety of gene regulatory mechanisms. As the most extensively studied ncRNA species, microRNAs (miRNAs) are important components in the oncogene and tumor suppressor network, and have been employed as potential biomarkers, therapeutic reagents, and therapeutic targets for cancer treatment. Other ncRNAs, particularly long noncoding RNAs, also have a profound impact on cancer development, as demonstrated in both mouse and human tumor models. We are only starting to understand the realm of ncRNA biology, and the exact molecular mechanisms governing ncRNA functions remain largely unexplored. With numerous ncRNAs discovered through high-throughput approaches, understanding their functions in malignant transformation will be one of the most exciting challenges in cancer research.
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p53: Multiple Facets of a Rubik's Cube
Vol. 1 (2017), pp. 185–201More LessThe p53 tumor suppressor has been studied for decades, and still there are many questions left unanswered. In this review, we first describe the current understanding of the wild-type p53 functions that determine cell survival or death, and regulation of the protein, with a particular focus on the negative regulators, the murine double minute family of proteins. We also summarize tissue-, stress-, and age-specific p53 activities and the potential underlying mechanisms. Among all p53 gene alterations identified in human cancers, p53 missense mutations predominate, suggesting an inherent biological advantage. Numerous gain-of-function activities of mutant p53 in different model systems and contexts have been identified. The emerging theme is that mutant p53, which retains a potent transcriptional activation domain, also retains the ability to modify gene transcription, albeit indirectly. Lastly, because mutant p53 stability is necessary for its gain of function, we summarize the mechanisms through which mutant p53 is specifically stabilized. A deeper understanding of the multiple pathways that impinge upon wild-type and mutant p53 activities and how these, in turn, regulate cell behavior will help identify vulnerabilities and therapeutic opportunities.
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Resisting Resistance
Vol. 1 (2017), pp. 203–221More LessTargeted therapies, immunotherapies, and improved chemotherapies are being developed to reduce the suffering and mortality that come from human cancer. Although these approaches, and in particular combinations of them, are expected to succeed eventually to a large degree, they all suffer one obstacle: Populations of replicating cells move away—typically in a high-dimensional space—from any opposing selection pressure they encounter. They evolve resistance. It is possible, however, to develop a precise mathematical understanding of the problem and to design treatment strategies that prevent resistance if possible or manage resistance otherwise. In this article, we present the fundamental equations that characterize the evolution of resistance. We provide formulas for the probability that resistant cells exist at the start of therapy, for the average number and sizes of resistant clones, and for the probability of successful combination treatment. We also demonstrate that developing new therapies that only maximize the killing rate of cancer cells may not be optimal, and that instead the parameters determining the fraction of resistant cells and their growth rate have a larger effect on the long-term control of cancer. These mathematical tools inform the search process for optimal therapies that aim to cure cancer.
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Deciphering Genetic Intratumor Heterogeneity and Its Impact on Cancer Evolution
Vol. 1 (2017), pp. 223–240More LessCancer is a disease reliant on the generation of mutations and the subsequent selection of those subpopulations endowed with the greatest fitness advantage. Beginning with a heterogeneous landscape of somatic alterations, various selective pressures acting on a tumor can shape the way it evolves. In this review, we first discuss the current bioinformatics tools available to tease apart the heterogeneous nature of a tumor and second consider the impact that evolutionary forces have on sculpting a tumor. Neighboring subclones may alter the microenvironment cultivating either cooperation or competition between clonal populations. Additionally, the harsh environment brought about by therapy and the immune system may force adaptation. Finally, we examine recent analyses focused on precancerous samples, which help to reveal clonal selection occurring during the earliest stages of tumor development, as well as work that has identified patterns of somatic evolution observed in normal tissues.
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Immune-Suppressing Cellular Elements of the Tumor Microenvironment
Vol. 1 (2017), pp. 241–255More LessDespite continual hints from preclinical and clinical research of its relevance, cancer immunology existed for many years at the periphery of cancer therapeutics. It is now the focus of intense and widespread interest after observations that blocking the activity of inhibitory receptors on T cells, known as T cell checkpoints, elicits durable clinical responses in many patients. The urgent challenge is now to understand the tissue-protective cellular elements of the tumor microenvironment (TME) that explain why the majority of patients do not respond to T cell checkpoint therapy. Analysis of human cancers and mouse models has shown that this nonresponsiveness is caused by the exclusion of T cells from the vicinity of cancer cells and that cells of the TME mediate this restriction. This review examines the immunosuppressive functions of the cells of the TME and discusses the steps of the antitumor immune reaction that, if inhibited, would diminish intratumoral T cell accumulation.
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Overcoming On-Target Resistance to Tyrosine Kinase Inhibitors in Lung Cancer
Vol. 1 (2017), pp. 257–274More LessAdvances in genomics, an improved understanding of malignant transformation, and the development of potent small molecule inhibitors capable of targeting key kinases have led to the adoption of genotype-guided approaches for the treatment of advanced cancers. As regulators of complex signaling networks, tyrosine kinases are among the most attractive targets. Moreover, insight into the conserved three-dimensional structures of these kinases and their mechanism of activation has facilitated the development of selective tyrosine kinase inhibitors (TKIs). TKIs have shown robust clinical activity in many different oncogene-addicted cancers; however, resistance invariably develops. In a significant proportion of patients, resistance results from acquired genetic alterations within the kinase target that allow cancer cells to escape TKI-mediated growth suppression. In this review, we discuss clinically observed and preclinical on-target resistance events in oncogene-driven solid tumors and describe current and future therapeutic strategies to overcome this type of resistance.
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Apoptosis and Cancer
Vol. 1 (2017), pp. 275–294More LessCancer is a disease involving the abnormal accumulation of cells resulting from an imbalance of proliferation and programmed cell death. This review focuses on the mitochondrial apoptotic pathway, a mechanism of programmed cell death with particular relevance to cancer. Starting over 30 years ago, basic findings in model organisms have been combined with findings in clinical cytogenetics to uncover a family of proteins, the BCL-2 family, that regulates the commitment to apoptosis by controlling permeabilization of the mitochondrial outer membrane. Cancer cells are generally more poised to engage the apoptotic machinery than normal cells are, a fact that likely underlies much of the therapeutic index exploited by many types of cancer chemotherapy. More recently, small molecules directly targeting the antiapoptotic proteins of the BCL-2 family have entered the clinic for testing in cancer. One therapeutic, venetoclax (ABT-199), has recently gained FDA approval in a landmark achievement for the apoptosis community. Important future efforts will be directed at building combinations of agents that selectively induce apoptosis in cancer cells.
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Chemical Carcinogenesis Models of Cancer: Back to the Future
Vol. 1 (2017), pp. 295–312More LessOver a century has elapsed since the first demonstration that exposure to chemicals in coal tar can cause cancer in animals. These observations provided an essential causal mechanistic link between environmental chemicals and increased risk of cancer in human populations. Mouse models of chemical carcinogenesis have since led to the concept of multistage tumor development through distinct stages of initiation, promotion, and progression and identified many of the genetic and biological events involved in these processes. Recent breakthroughs in DNA sequencing have now given us tools to dissect complete tumor genome architectures and revealed that chemically induced cancers in the mouse carry a high point mutation load and mutation signatures that reflect the causative agent used for tumor induction. Chemical carcinogenesis models may therefore provide a route to identify the causes of mutation signatures found in human cancers and further inform studies of therapeutic drug resistance and responses to immunotherapy, which are dependent on mutation load and genetic heterogeneity.
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Extracellular Matrix Remodeling and Stiffening Modulate Tumor Phenotype and Treatment Response
Vol. 1 (2017), pp. 313–334More LessSolid tumors are characterized by a remodeled and stiffened extracellular matrix. The extracellular matrix is not a passive by-product of the tumor, but actively compromises tissue-specific differentiation, enhances tumor cell proliferation and survival, and fosters tumor cell invasion and migration. The tumor extracellular matrix also influences the behavior of the stromal cells, which through vicious, feedforward-reinforcing pathways promote tumor progression and compromise treatment efficacy. To investigate how the tumor extracellular matrix alters cancer phenotype and treatment, a number of three-dimensional, organotypic culture models have been developed that employ a variety of materials, including natural matrices, collagen, fibrin, and reconstituted basement membrane gels, as well as synthetic hydrogel materials such as polyacrylamide and polyethylene glycol. These models have been used to interrogate how specific microenvironmental features modify tumor and stromal cell function and to identify the molecular mechanisms that regulate tumorigenesis and therapeutic efficacy. To translate these findings into more effective treatment strategies for patients, clinically informed studies are needed that incorporate computational modeling and in vivo validation.
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Aneuploidy in Cancer: Seq-ing Answers to Old Questions
Vol. 1 (2017), pp. 335–354More LessAneuploidy, the state of having gained or lost chromosomes, is a hallmark of cancer. Approximately 90% of tumors have gained or lost at least one chromosome. In spite of aneuploidy occurring as frequently as, if not more often than, disruption of the p53 pathway, whether and how aneuploidy influences tumorigenesis is still poorly understood. Here, we take advantage of large-scale tumor sequencing efforts to assess karyotypic alterations across many cancer types and review recent sequencing studies that show how karyotypes change in space and time. We further summarize findings that describe the effects of aneuploidy on untransformed cells, the mechanisms by which aneuploidy could drive tumorigenesis, and the potential to target aneuploidy for cancer therapy.
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The Role of Chromatin-Associated Proteins in Cancer
Vol. 1 (2017), pp. 355–377More LessThe organization of the chromatin structure is essential for maintaining cell-type-specific gene expression and therefore for cell identity. This structure is highly dynamic and is regulated by a large number of chromatin-associated proteins that are required for normal development and differentiation. Recurrent somatic mutations have been found with high frequency in genes coding for chromatin-associated proteins in cancer, and several of these are required for cancer maintenance. In this review, we discuss recent advances in understanding the role of chromatin-associated proteins in transcription, development, and cancer. Specifically, we focus on selected examples of proteins belonging to the histone methyltransferase, histone demethylase, or bromodomain families, for which specific small molecule inhibitors have been developed and are in either preclinical or clinical trials.
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