Showing papers in "Trends in cancer in 2015"
TL;DR: This work reviews the metastatic traits that allow cancer cells to colonize distinct organ sites and the bottlenecks that challenge cancer cells in newly invaded microenvironments are organ-specific and consequently demand distinct mechanisms for metastatic colonization.
Abstract: 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.
380 citations
TL;DR: The features and functions of the distinct GBM niches are reviewed, the different cell constituents and the functional status of the vasculature are detailed, and prospects of therapeutically targeting GBM niche constituents are discussed.
Abstract: Glioblastomas (GBM) are one of the most recalcitrant brain tumors because of their aggressive invasive growth and resistance to therapy. They are highly heterogeneous malignancies at both the molecular and histological levels. Specific histological hallmarks including pseudopalisading necrosis and microvascular proliferation distinguish GBM from lower-grade gliomas, and make GBM one of the most hypoxic as well as angiogenic tumors. These microanatomical compartments present specific niches within the tumor microenvironment that regulate metabolic needs, immune surveillance, survival, invasion as well as cancer stem cell maintenance. Here we review features and functions of the distinct GBM niches, detail the different cell constituents and the functional status of the vasculature, and discuss prospects of therapeutically targeting GBM niche constituents.
316 citations
TL;DR: Recent advances in understanding of TFs as drug targets in oncology are discussed, with an emphasis on the emerging chemical approaches to modulate TF function.
Abstract: Transcription factors (TFs) are commonly deregulated in the pathogenesis of human cancer and are a major class of cancer cell dependencies. Consequently, targeting of TFs can be highly effective in treating particular malignancies, as highlighted by the clinical efficacy of agents that target nuclear hormone receptors. In this review we discuss recent advances in our understanding of TFs as drug targets in oncology, with an emphasis on the emerging chemical approaches to modulate TF function. The remarkable diversity and potency of TFs as drivers of cell transformation justifies a continued pursuit of TFs as therapeutic targets for drug discovery.
229 citations
TL;DR: Emerging modalities of lncRNA biology and their interplay with cancer-associated concepts are discussed, including epigenetic regulation, DNA damage and cell cycle control, microRNA silencing, signal transduction pathways, and hormone-driven disease.
Abstract: While our understanding of the molecular mechanisms underlying cancer has significantly improved, most of our knowledge focuses on protein-coding genes that make up a fraction of the genome. Recent studies have uncovered thousands of long noncoding RNAs (lncRNAs) that populate the cancer genome. A subset of these molecules shows striking cancer- and lineage-specific expression patterns, suggesting they may be potential drivers of cancer biology and have utility as clinical biomarkers. Here, we discuss emerging modalities of lncRNA biology and their interplay with cancer-associated concepts, including epigenetic regulation, DNA damage and cell cycle control, microRNA silencing, signal transduction pathways, and hormone-driven disease. Additionally, we highlight the translational impact of lncRNAs, tools for their mechanistic investigation, and directions for future lncRNA research.
216 citations
TL;DR: Recent insights into the biological properties of individual and clustered cancer cells in the circulation are discussed, including changes in expression of epithelial and mesenchymal markers which may show dynamic changes during cancer progression.
Abstract: Blood-borne metastasis accounts for the vast majority of cancer-related deaths and it is fueled by the generation of circulating tumor cells (CTCs) from a primary tumor deposit. Recent technological advances have made it possible to characterize human CTCs as they travel within the bloodstream. CTCs are found both as single cells and as clusters of cells held together by intercellular junctions. Although less prevalent, CTC clusters appear to have greater metastatic potential than single CTCs in the circulation. Both may exhibit shifts in expression of epithelial and mesenchymal markers, which may show dynamic changes during cancer progression. In this review we discuss recent insights into the biological properties of individual and clustered cancer cells in the circulation.
212 citations
TL;DR: Treatments targeting ALT may hold promise for a broadly applicable therapeutic modality specific to mesenchymal lineage tumors, something that has thus far remained elusive.
Abstract: Activation of a telomere maintenance mechanism (TMM) is permissive for replicative immortality and a hallmark of human cancer. While most cancers rely on reactivation of telomerase, a significant fraction utilizes the recombination dependent alternative lengthening of telomeres (ALT) pathway. ALT is enriched in tumors of mesenchymal origin, including those arising from bone, soft tissue, and the nervous system, and usually portends a poor prognosis. Recent insights into the mechanisms of ALT are uncovering novel avenues to exploit vulnerabilities and may facilitate clinical development of ALT detection assays and personalized treatment decisions based on TMM status. Treatments targeting ALT may hold promise for a broadly applicable therapeutic modality specific to mesenchymal lineage tumors, something that has thus far remained elusive.
177 citations
TL;DR: This work reviews the novel concept of "collateral lethality", which has served to identify cancer-specific therapeutic vulnerabilities resulting from co-deletion of passenger genes neighboring TSG and offers novel opportunities for the development of personalized anti-neoplastic therapies.
Abstract: Genomic deletion of tumor suppressor genes (TSGs) is a rite of passage for virtually all human cancers. The synthetic lethal paradigm has provided a framework for the development of molecular targeted therapeutics that are functionally linked to the loss of specific TSG functions. In the course of genomic events that delete TSGs, a large number of genes with no apparent direct role in tumor promotion also sustain deletion as a result of chromosomal proximity to the target TSG. In this perspective, we review the novel concept of ‘collateral lethality', which has served to identify cancer-specific therapeutic vulnerabilities resulting from codeletion of passenger genes neighboring TSGs. The large number of collaterally deleted genes, playing diverse functions in cell homeostasis, offers a rich repertoire of pharmacologically targetable vulnerabilities presenting novel opportunities for the development of personalized antineoplastic therapies.
103 citations
TL;DR: The prospects and challenges of drugging oncogenic RAS are discussed, and new inhibitors of RAS effector signaling and the ERK mitogen-activated protein kinase cascade are focused on.
Abstract: The three RAS genes comprise the most frequently mutated oncogene family in cancer. With significant and compelling evidence that continued function of mutant RAS is required for tumor maintenance, it is widely accepted that effective anti-RAS therapy will have a significant impact on cancer growth and patient survival. However, despite more than three decades of intense research and pharmaceutical industry efforts, a clinically effective anti-RAS drug has yet to be developed. With the recent renewed interest in targeting RAS, exciting and promising progress has been made. In this review, we discuss the prospects and challenges of drugging oncogenic RAS. In particular, we focus on new inhibitors of RAS effector signaling and the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) cascade.
100 citations
TL;DR: An interpretation of mechanisms contributing to the carcinogenicity of these helminth infections, including roles for metabolites of catechol estrogen and oxysterols of parasite origin as initiators of carcinogenesis are presented.
Abstract: Infections with Opisthorchis viverrini, Clonorchis sinensis, and Schistosoma haematobium are classified as group 1 biological carcinogens: definitive causes of cancer. These worms are metazoan eukaryotes, unlike the other group 1 carcinogens including human papilloma virus, hepatitis C virus, and Helicobacter pylori. By contrast, infections with phylogenetic relatives of these helminths, also trematodes of the phylum Platyhelminthes and major human pathogens, are not carcinogenic. These inconsistencies prompt several questions, including how might these infections cause cancer, and why is infection with only a few helminth species carcinogenic? We present an interpretation of mechanisms contributing to the carcinogenicity of these helminth infections, including roles for metabolites of catechol estrogen and oxysterols of parasite origin as initiators of carcinogenesis.
89 citations
TL;DR: A review of immune-mediated mechanisms underlying the efficacy of chemotherapy and radiotherapy can be found in this article, which provides a perspective on how understanding tissue-based immune mechanisms can be used to guide therapeutic approaches combining immune and cytotoxic therapies to improve outcomes for a larger subset of patients than is currently achievable.
Abstract: Chemotherapy and radiotherapy have been extensively used to eradicate cancer based on their direct cytocidal effects on rapidly proliferating tumor cells. Accumulating evidence indicates that these therapies also dramatically affect resident and recruited immune cells that actively support tumor growth. We now appreciate that mobilization of effector CD8 + T cells enhances the efficacy of chemotherapy and radiotherapy; remarkable clinical advances have been achieved by blocking regulatory programs limiting cytotoxic CD8 + T cell activity. This review discusses immune-mediated mechanisms underlying the efficacy of chemotherapy and radiotherapy, and provides a perspective on how understanding tissue-based immune mechanisms can be used to guide therapeutic approaches combining immune and cytotoxic therapies to improve outcomes for a larger subset of patients than is currently achievable.
82 citations
TL;DR: Whether this emerging field of research is a 'mirage' without a clear picture, or truly represents a paradigm shift for cancer research, is posed.
Abstract: Investigations focused on the interplay between the human microbiome and cancer development, herein termed the ‘oncobiome’, have been growing at a rapid rate. However, these studies to date have primarily demonstrated associative relationships rather than causative ones. We pose the question of whether this emerging field of research is a ‘mirage’ without a clear picture, or truly represents a paradigm shift for cancer research. We propose the necessary steps needed to answer crucial questions and push the field forward to bring the mirage into a tangible reality.
TL;DR: This review outlines the understanding of the alterations in signaling pathways that simultaneously contribute to the malignant phenotype and virus-mediated killing of cancer cells.
Abstract: Tumor cells harbor tens to thousands of genetic and epigenetic alterations that disrupt cellular pathways, providing them with growth and survival advantages. However, these benefits come at a cost, with uncontrolled cell growth, defective apoptosis, sustained pathological angiogenesis, immune evasion, and a metastatic phenotype occurring at the expense of the antiviral response of the individual tumor cell. Oncolytic virotherapy is an emerging therapeutic strategy that uses replication-competent viruses to selectivity kill cancer cells by exploiting their impaired antiviral response. In this review, we outline our understanding of the alterations in signaling pathways that simultaneously contribute to the malignant phenotype and virus-mediated killing of cancer cells.
TL;DR: This review will focus on recent reports of the involvement of the ABL kinases in tumor progression using mouse models as well as recent data generated from genomic and proteomic studies linking enhanced expression and hyper-activation of the H2O kinases to some human cancers.
Abstract: The Abelson (ABL) tyrosine kinases were identified as drivers of leukemia in mice and humans. Emerging data has shown a role for the ABL family kinases, ABL1 and ABL2, in the progression of several solid tumors. This review will focus on recent reports of the involvement of the ABL kinases in tumor progression using mouse models as well as recent data generated from genomic and proteomic studies linking enhanced expression and hyper-activation of the ABL kinases to some human cancers. Preclinical studies on small molecule inhibitors of the ABL kinases suggest that their use may have beneficial effects for the treatment of selected solid tumors.
TL;DR: Recent progress is reviewed in understanding how certain distinctive features of the cancer genome, including clustered mutagenesis, tandem segmental duplications, complex breakpoints, chromothripsis, chromoplexy and chromoanasynthesis may arise.
Abstract: Chromosome rearrangement plays a causal role in tumorigenesis by contributing to the inactivation of tumor suppressor genes, the dysregulated expression or amplification of oncogenes and the generation of novel gene fusions. Chromosome breaks are important intermediates in this process. How, when and where these breaks arise and the specific mechanisms engaged in their repair strongly influence the resulting patterns of chromosome rearrangement. Here, we review recent progress in understanding how certain distinctive features of the cancer genome, including clustered mutagenesis, tandem segmental duplications, complex breakpoints, chromothripsis, chromoplexy and chromoanasynthesis may arise.
TL;DR: Recent developments in deciphering the cellular origins of solid cancers are reviewed, with a focus on stem and progenitor cells.
Abstract: Intertumoral heterogeneity is driven by a combination of intrinsic and extrinsic mechanisms. Intrinsic mechanisms include the genetic/epigenetic mutational profile of cells and the nature of the 'cell of origin'. There is accumulating evidence that distinct 'cells of origin' within an organ can give rise to different subtypes of cancer. Tissue-specific stem and progenitor cells are the predominant targets exploited for tumor initiation. Extrinsic factors imposed by the microenvironment may also directly influence the cell of origin by eliciting dedifferentiation. Identification of these target cell populations is important for earlier diagnosis, the detection of premalignant clones during relapse, and the design of prevention therapies for high-risk cancer families. Here we review recent developments in deciphering the cellular origins of solid cancers.
TL;DR: The impact of abnormal karyotypes on oncogenesis, tumor progression, and response to treatment is discussed, focusing on the biochemical and metabolic liabilities of non-diploid cells that can be harnessed for the development of novel chemo(immuno)therapeutic regimens against cancer.
Abstract: The propagation of whole-chromosome (aneuploid) or whole-genome (polyploid) defects is normally prevented by robust cell-intrinsic mechanisms. Moreover, non-diploid cells are under strict immunological surveillance. Nonetheless, tumors contain a high percentage of non-diploid genomes, indicating that malignant cells acquire the ability to bypass these control mechanisms and obtain a survival/proliferation benefit from bulky karyotypic defects. The non-diploid state imposes a significant metabolic burden on cancer cells and hence can be selectively targeted for therapeutic purposes. Here we discuss the impact of abnormal karyotypes on oncogenesis, tumor progression, and response to treatment, focusing on the biochemical and metabolic liabilities of non-diploid cells that can be harnessed for the development of novel chemo(immuno)therapeutic regimens against cancer.
TL;DR: This review addresses how tumor clonality is measured using next-generation sequencing (NGS) data, highlights that clonal heterogeneity is common across multiple tumor types, and discusses the potential clinical implications of tumorClonal heterogeneity.
Abstract: Recent whole-genome sequencing (WGS) studies have demonstrated that tumors typically comprise a founding clone and multiple subclones (i.e., clonal heterogeneity is common). The possible combination of mutations in each tumor clone is enormous, making each tumor genetically unique. Clonal heterogeneity likely has a role in cancer progression, relapse, metastasis, and chemoresistance due to functional differences in genetically unique subclones. In current clinical practice, gene mutations are only classified as being present or absent, ignoring the clonal complexity of cancers. In this review, we address how tumor clonality is measured using next-generation sequencing (NGS) data, highlight that clonal heterogeneity is common across multiple tumor types, and discuss the potential clinical implications of tumor clonal heterogeneity.
TL;DR: The interactions among various cell populations in both normal and tumor tissues are discussed, and a better understanding of these interactions will be important for the development of improved combinatorial therapies designed to prevent relapse and to ultimately decrease mortality.
Abstract: Breast cancer is no longer considered a single disease, but instead is made up of multiple subtypes with genetically and most likely epigenetically heterogeneous tumors composed of numerous clones. Both the hierarchical cancer stem cell and clonal evolution models have been invoked to help explain this intratumoral heterogeneity. Several recent studies have helped define the functional interactions among the different cellular subpopulations necessary for the evolution of this complex ecosystem. These interactions involve paracrine interactions that include locally acting Wnt family members, reminiscent of the signaling pathways important for normal mammary gland development and stem cell self-renewal. In this review, we discuss the interactions among various cell populations in both normal and tumor tissues. A better understanding of these interactions, especially in the metastatic setting, will be important for the development of improved combinatorial therapies designed to prevent relapse and to ultimately decrease mortality.
TL;DR: The incomplete fidelity of the mouse system in modeling human hematopoietic cells is reviewed, and advances that portend a shift towards studies focused directly on human cells are highlighted.
Abstract: Similarities between the organization of the blood-forming system in humans and mice, and the ease of genetically manipulating and assessing primitive mouse hematopoietic cells, has made this species a model of choice. However, important differences exist in the role of specific gene products in regulating analogous steps in the generation of particular blood cell types in humans and mice, as well as in the perturbations that the same mutations elicit in hematopoietic cells from the two species. At the same time, the methods to generate and propagate normal and genetically altered human hematopoietic cells are increasingly permissive, and progress towards humanized mice is advancing rapidly. We review the incomplete fidelity of the mouse system in modeling human hematopoiesis, and highlight advances that portend a shift towards studies focused directly on human cells.
TL;DR: Novel strategies that use genome-wide chromatin structure profiling to identify the deregulated factors on which cancer cells depend, with the ultimate aim of targeting them are highlighted.
Abstract: Cancer is primarily caused by mutations in genes encoding transcriptional regulators and signaling molecules. These mutations cooperate to deregulate the tight control over gene expression that is otherwise seen in normal cells. One consequence of this process is deregulated transcription factor (TF) activity. This forum article highlights novel strategies that use genome-wide chromatin structure profiling to identify the deregulated factors on which cancer cells depend, with the ultimate aim of targeting them.
TL;DR: Global analyses of cancer transcriptomes demonstrate that ADAR (adenosine deaminase, RNA-specific)-mediated RNA editing dynamically contributes to genetic alterations in cancer, and directly correlates with progression and prognosis.
Abstract: Global analyses of cancer transcriptomes demonstrate that ADAR (adenosine deaminase, RNA-specific)-mediated RNA editing dynamically contributes to genetic alterations in cancer, and directly correlates with progression and prognosis. RNA editing is abundant and frequently elevated in cancer, and affects functionally and clinically relevant sites in both coding and non-coding regions of the transcriptome. Therefore, ADAR and differentially edited transcripts may be promising biomarkers or targets for therapy.
TL;DR: An adaptive learning platform, APOLLO™ (adaptive patient-oriented longitudinal learning and optimization) designed to integrate genomic research in the context of, but not in the path of, routine and investigational clinical care for purposes of enabling data-driven discovery across disciplines such that every patient can contribute to and potentially benefit from research discoveries.
Abstract: Precision medicine requires appropriate application of genomics in clinical practice. In cancer, we have witnessed practice-changing examples of how genomic knowledge is translated into more tailored and effective therapies. The next opportunity is to embed cancer genomics in clinical context so that patient-centric longitudinal clinical, genomic, and molecular phenotypes can be compiled for adaptive learning between precision medicine research and clinical care with the goal of accelerating clinically-actionable discoveries. We describe here an adaptive learning platform, APOLLO™ (adaptive patient-oriented longitudinal learning and optimization) designed to integrate genomic research in the context of, but not in the path of, routine and investigational clinical care for purposes of enabling data-driven discovery across disciplines such that every patient can contribute to and potentially benefit from research discoveries.
TL;DR: Evidence is presented here that essential micronutrients have a direct effect on H. pylori virulence, which subsequently affects interactions at the host-pathogen interface, thereby facilitating the development of premalignant and malignant lesions in the stomach.
Abstract: Epidemiologic studies throughout the world have uniformly demonstrated significant relationships between the intake of dietary micronutrients and gastric cancer risk. An exciting concept that has gained considerable traction recently is that micronutrients modulate gene expression within Helicobacter pylori, the strongest identified risk factor for gastric carcinogenesis. We present evidence here that essential micronutrients have a direct effect on H. pylori virulence, which subsequently affects interactions at the host-pathogen interface, thereby facilitating the development of premalignant and malignant lesions in the stomach. Further, these fundamental concepts provide a framework for understanding mechanisms driving the development of other malignancies that arise from foci of gastrointestinal inflammation.
TL;DR: It is 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.
Abstract: 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.
TL;DR: An integrated genomic approach was used to identify the Ras-related nuclear protein (RAN) pathway as being integral in neuroblastoma pathogenesis and provided compelling validation for a role of the LIN28B-RAN-Aurora Kinase A (AURKA) pathway in Neuroblastoma.
Abstract: Despite major advances in the genomics of neuroblastoma, high-risk patients still have considerable morbidity and mortality even with aggressive chemotherapy. In a recent article published in Cancer Cell, Schnepp et al. used an integrated genomic approach to identify the Ras-related nuclear protein (RAN) pathway as being integral in neuroblastoma pathogenesis and provided compelling validation for a role of the LIN28B-RAN-Aurora Kinase A (AURKA) pathway in neuroblastoma. This opens the door to less-toxic and more-effective therapy for high-risk neuroblastoma in the near future.