Showing papers in "Nature Reviews Cancer in 2010"
TL;DR: Clinical developments emphasize the need to identify how integrin antagonists influence the tumour and its microenvironment.
Abstract: The integrin family of cell adhesion receptors regulates a diverse array of cellular functions crucial to the initiation, progression and metastasis of solid tumours. The importance of integrins in several cell types that affect tumour progression has made them an appealing target for cancer therapy. Integrin antagonists, including the alphavbeta3 and alphavbeta5 inhibitor cilengitide, have shown encouraging activity in Phase II clinical trials and cilengitide is currently being tested in a Phase III trial in patients with glioblastoma. These exciting clinical developments emphasize the need to identify how integrin antagonists influence the tumour and its microenvironment.
2,894 citations
TL;DR: There is now substantial evidence for the importance of FGF signalling in the pathogenesis of diverse tumour types, and clinical reagents that specifically target the FGFs or FGF receptors are being developed.
Abstract: Fibroblast growth factors (FGFs) and their receptors control a wide range of biological functions, regulating cellular proliferation, survival, migration and differentiation. Although targeting FGF signalling as a cancer therapeutic target has lagged behind that of other receptor tyrosine kinases, there is now substantial evidence for the importance of FGF signalling in the pathogenesis of diverse tumour types, and clinical reagents that specifically target the FGFs or FGF receptors are being developed. Although FGF signalling can drive tumorigenesis, in different contexts FGF signalling can mediate tumour protective functions; the identification of the mechanisms that underlie these differential effects will be important to understand how FGF signalling can be most appropriately therapeutically targeted.
2,211 citations
TL;DR: Cilengitide is an inhibitor of both αvβ3 and αv β5 integrins, and it was selected in the laboratory by screening a library of cyclic RGD peptides in a cell-free receptor assay for their capacity to inhibit Integrins αvα3 andαvβ5 but not αΙΙbβ3 REF.
Abstract: Nature Reviews Cancer 10, 9–22 (2010) On page 17 of this article, in the section Targeting αvβ3 and αvβ5 the sentence at the start of the second paragraph that reads “Cilengitide is an inhibitor of both αvβ3 and αvβ5 integrins, and it was selected in our laboratory by screening a library of cyclic RGD peptides in a cell-free receptor assay for their capacity to inhibit integrins αvβ3 and αvβ5 but not αΙΙbβ3 REF.
1,657 citations
TL;DR: Understanding the molecular mechanisms underlying the role of prostaglandins and other eicosanoids in cancer progression will help to develop more effective cancer chemopreventive and/or therapeutic agents.
Abstract: Eicosanoids, including prostaglandins and leukotrienes, are biologically active lipids that have been implicated in various pathological processes, such as inflammation and cancer. This Review highlights our understanding of the intricate roles of eicosanoids in epithelial-derived tumours and their microenvironment. The knowledge of how these lipids orchestrate the complex interactions between transformed epithelial cells and the surrounding stromal cells is crucial for understanding tumour evolution, progression and metastasis. Understanding the molecular mechanisms underlying the role of prostaglandins and other eicosanoids in cancer progression will help to develop more effective cancer chemopreventive and/or therapeutic agents.
1,539 citations
TL;DR: Understanding how HPV oncoproteins modify these activities provides novel insights into the basic mechanisms of oncogenesis, which are crucial regulators of cell cycle progression, telomere maintenance, apoptosis and chromosomal stability.
Abstract: An association between human papillomavirus (HPV) infection and the development of cervical cancer was initially reported over 30 years ago, and today there is overwhelming evidence that certain subtypes of HPV are the causative agents of these malignancies. The p53 and retinoblastoma proteins are well-characterized targets of the HPV E6 and E7 oncoproteins, but recent studies have shown that the alteration of additional pathways are equally important for transformation. These additional factors are crucial regulators of cell cycle progression, telomere maintenance, apoptosis and chromosomal stability. Understanding how HPV oncoproteins modify these activities provides novel insights into the basic mechanisms of oncogenesis.
1,476 citations
TL;DR: The molecular chaperone heat shock protein 90 (HSP90) has been used by cancer cells to facilitate the function of numerous oncoproteins, and it can be argued that cancer cells are 'addicted' to HSP90.
Abstract: The molecular chaperone heat shock protein 90 (HSP90) has been used by cancer cells to facilitate the function of numerous oncoproteins, and it can be argued that cancer cells are 'addicted' to HSP90. However, although recent reports of the early clinical efficacy of HSP90 inhibitors are encouraging, the optimal use of HSP90-targeted therapeutics will depend on understanding the complexity of HSP90 regulation and the degree to which HSP90 participates in both neoplastic and normal cellular physiology.
1,341 citations
TL;DR: What is known about the structures and functions of the family ofPARP enzymes are reviewed, and a series of questions that should be addressed are outlined to guide the rational development of PARP inhibitors as anticancer agents.
Abstract: Recent findings have thrust poly(ADP-ribose) polymerases (PARPs) into the limelight as potential chemotherapeutic targets. To provide a framework for understanding these recent observations, we review what is known about the structures and functions of the family of PARP enzymes, and then outline a series of questions that should be addressed to guide the rational development of PARP inhibitors as anticancer agents.
1,200 citations
TL;DR: In reviewing this new field of cancer biology, the methodological approaches of these studies are described, and recommendations for which strategies will be most informative in the future are made.
Abstract: The presence of single nucleotide polymorphisms in microRNA genes, their processing machinery and target binding sites might affect cancer risk, treatment efficacy and patient prognosis. This evolving field of cancer biology is discussed in this Review.
1,190 citations
TL;DR: This Review discusses how numerous cellular context-dependent factors maintain the balance of TGFβ signalling and how their collapse leads to tumour progression.
Abstract: The distortion of growth factor signalling is the most important prerequisite in tumour progression. Transforming growth factor-beta (TGFbeta) signalling regulates tumour progression by a tumour cell-autonomous mechanism or through tumour-stroma interaction, and has either a tumour-suppressing or tumour-promoting function depending on cellular context. Such inherent complexity of TGFbeta signalling results in arduous, but promising, assignments for developing therapeutic strategies against malignant tumours. As numerous cellular context-dependent factors tightly maintain the balance of TGFbeta signalling and contribute to the regulation of TGFbeta-induced cell responses, in this Review we discuss how they maintain the balance of TGFbeta signalling and how their collapse leads to tumour progression.
1,069 citations
TL;DR: The Eph receptor tyrosine kinases and their ephrin ligands have intriguing expression patterns in cancer cells and tumour blood vessels, which suggest important roles for their bidirectional signals in many aspects of cancer development and progression.
Abstract: The Eph receptor tyrosine kinases and their ephrin ligands have intriguing expression patterns in cancer cells and tumour blood vessels, which suggest important roles for their bidirectional signals in many aspects of cancer development and progression. Eph gene mutations probably also contribute to cancer pathogenesis. Eph receptors and ephrins have been shown to affect the growth, migration and invasion of cancer cells in culture as well as tumour growth, invasiveness, angiogenesis and metastasis in vivo. However, Eph signalling activities in cancer seem to be complex, and are characterized by puzzling dichotomies. Nevertheless, the Eph receptors are promising new therapeutic targets in cancer.
1,067 citations
TL;DR: Recent advances in understanding the interpretation of certain histone methylations by plant homeodomain finger-containing proteins are summarized, and how misreading, miswriting and mis-erasing of hist one methylation marks can be associated with oncogenesis and progression are summarized.
Abstract: Post-translational modification of histones provides an important regulatory platform for processes such as gene transcription and DNA damage repair. It has become increasingly apparent that the misregulation of histone modification, which is caused by the deregulation of factors that mediate the modification installation, removal and/or interpretation, actively contributes to human cancer. In this Review, we summarize recent advances in understanding the interpretation of certain histone methylations by plant homeodomain finger-containing proteins, and how misreading, miswriting and mis-erasing of histone methylation marks can be associated with oncogenesis and progression. These observations provide us with a greater mechanistic understanding of epigenetic alterations in human cancers and might also help direct new therapeutic interventions in the future.
TL;DR: This Review highlights pathways against which there are already drugs in different stages of development and also discusses additional druggable targets.
Abstract: Cancer therapy has long relied on the rapid proliferation of tumour cells for effective treatment. However, the lack of specificity in this approach often leads to undesirable side effects. Many reports have described various 'metabolic transformation' events that enable cancer cells to survive, suggesting that metabolic pathways might be good targets. There are currently several drugs under development or in clinical trials that are based on specifically targeting the altered metabolic pathways of tumours. This Review highlights pathways against which there are already drugs in different stages of development and also discusses additional druggable targets.
TL;DR: The importance of cellular senescence, which is a stress response that stably blocks proliferation, is increasingly being recognized and translating these concepts to clinical oncology remains a challenge.
Abstract: The importance of cellular senescence, which is a stress response that stably blocks proliferation, is increasingly being recognized. Senescence is prevalent in pre-malignant tumours, and progression to malignancy requires evading senescence. Malignant tumours, however, may still undergo senescence owing to interventions that restore tumour suppressor function or inactivate oncogenes. Senescent tumour cells can be cleared by immune cells, which may result in efficient tumour regression. Standard chemotherapy also has the potential to induce senescence, which may partly underlie its therapeutic activity. Although these concepts are well supported in mouse models, translating them to clinical oncology remains a challenge.
TL;DR: This Review summarizes recent developments aimed at treating and ultimately curing Epidermal growth factor receptor-mutant lung cancer.
Abstract: Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) was first recognized in 2004 as a distinct, clinically relevant molecular subset of lung cancer. The disease has been the subject of intensive research at both the basic scientific and clinical levels, becoming a paradigm for how to understand and treat oncogene-driven carcinomas. Although patients with EGFR-mutant tumours have increased sensitivity to tyrosine kinase inhibitors (TKIs), primary and acquired resistance to these agents remains a major clinical problem. This Review summarizes recent developments aimed at treating and ultimately curing the disease.
TL;DR: It is proposed that delineating the precise roles of these transporters in tumorigenesis and treatment response will be important for the development of more effective targeted therapies.
Abstract: Multidrug transporter proteins are best known for their contributions to chemoresistance through the efflux of anticancer drugs from cancer cells. However, a considerable body of evidence also points to their importance in cancer extending beyond drug transport to fundamental roles in tumour biology. Currently, much of the evidence for these additional roles is correlative and definitive studies are needed to confirm causality. We propose that delineating the precise roles of these transporters in tumorigenesis and treatment response will be important for the development of more effective targeted therapies.
TL;DR: Delineation of bacterial and host mediators that augment gastric cancer risk has profound ramifications for both physicians and biomedical researchers as such findings will not only focus the prevention approaches that target H. pylori-infected human populations at increased risk for stomach cancer but also provide mechanistic insights into inflammatory carcinomas that develop beyond the gastric niche.
Abstract: Helicobacter pyloricauses gastric adenocarcinoma in a minority of infected individuals. What have we learned about bacterial and host-specific factors that lead to malignancy, and what canH. pyloritell us about inflammatory carcinomas that develop beyond the gastric niche? Helicobacter pylori is the dominant species of the human gastric microbiome, and colonization causes a persistent inflammatory response. H. pylori-induced gastritis is the strongest singular risk factor for cancers of the stomach; however, only a small proportion of infected individuals develop malignancy. Carcinogenic risk is modified by strain-specific bacterial components, host responses and/or specific host–microbe interactions. Delineation of bacterial and host mediators that augment gastric cancer risk has profound ramifications for both physicians and biomedical researchers as such findings will not only focus the prevention approaches that target H. pylori-infected human populations at increased risk for stomach cancer but will also provide mechanistic insights into inflammatory carcinomas that develop beyond the gastric niche.
TL;DR: Microtubules are dynamic structures composed of α–β-tubulin heterodimers that are essential in cell division and are important targets for cancer drugs and understanding the molecular mechanisms that mediate resistance to tubulin-binding agents will help improve the efficacy of these agents.
Abstract: Microtubules are dynamic structures composed of alpha-beta-tubulin heterodimers that are essential in cell division and are important targets for cancer drugs. Mutations in beta-tubulin that affect microtubule polymer mass and/or drug binding are associated with resistance to tubulin-binding agents such as paclitaxel. The aberrant expression of specific beta-tubulin isotypes, in particular betaIII-tubulin, or of microtubule-regulating proteins is important clinically in tumour aggressiveness and resistance to chemotherapy. In addition, changes in actin regulation can also mediate resistance to tubulin-binding agents. Understanding the molecular mechanisms that mediate resistance to tubulin-binding agents will be vital to improve the efficacy of these agents.
TL;DR: There is substantial evidence that sphingosine 1-phosphate (S1P) is involved in cancer and the potential for new therapeutics designed to alter S1P signalling and function in cancer is examined.
Abstract: There is substantial evidence that sphingosine 1-phosphate (S1P) is involved in cancer. S1P regulates processes such as inflammation, which can drive tumorigenesis; neovascularization, which provides cancer cells with nutrients and oxygen; and cell growth and survival. This occurs at multiple levels and involves S1P receptors, sphingosine kinases, S1P phosphatases and S1P lyase. This Review summarizes current research findings and examines the potential for new therapeutics designed to alter S1P signalling and function in cancer.
TL;DR: Clinical efforts are underway to target specific components of the translation apparatus or unique mRNA translation elements for cancer therapeutics to define a new understanding of the role of mRNA translation and protein synthesis in human cancer.
Abstract: Remarkable progress has been made in defining a new understanding of the role of mRNA translation and protein synthesis in human cancer. Translational control is a crucial component of cancer development and progression, directing both global control of protein synthesis and selective translation of specific mRNAs that promote tumour cell survival, angiogenesis, transformation, invasion and metastasis. Translational control of cancer is multifaceted, involving alterations in translation factor levels and activities unique to different types of cancers, disease stages and the tumour microenvironment. Several clinical efforts are underway to target specific components of the translation apparatus or unique mRNA translation elements for cancer therapeutics.
TL;DR: It is discussed how the modulation of ribosome biogenesis by MYC may be essential to its physiological functions as well as its pathological role in tumorigenesis.
Abstract: Recently, MYC has been shown to serve as a direct regulator of ribosome biogenesis and therefore coordinates protein synthesis. Could the regulation of ribosome biogenesis by MYC be necessary for its role in tumorigenesis? MYC regulates the transcription of thousands of genes required to coordinate a range of cellular processes, including those essential for proliferation, growth, differentiation, apoptosis and self-renewal. Recently, MYC has also been shown to serve as a direct regulator of ribosome biogenesis. MYC coordinates protein synthesis through the transcriptional control of RNA and protein components of ribosomes, and of gene products required for the processing of ribosomal RNA, the nuclear export of ribosomal subunits and the initiation of mRNA translation. We discuss how the modulation of ribosome biogenesis by MYC may be essential to its physiological functions as well as its pathological role in tumorigenesis.
TL;DR: Recent studies indicate that IAPs not only regulate caspases and apoptosis, but also modulate inflammatory signalling and immunity, mitogenic kinase signalling, proliferation and mitosis, as well as cell invasion and metastasis.
Abstract: The realization that alterations in inhibitor of apoptosis (IAP) proteins are found in many types of human cancer and are associated with chemoresistance, disease progression and poor prognosis, has sparked a worldwide frenzy in the development of small pharmacological inhibitors of IAPs. The development of such inhibitors has radically changed our knowledge of the signalling processes that are regulated by IAPs. Recent studies indicate that IAPs not only regulate caspases and apoptosis, but also modulate inflammatory signalling and immunity, mitogenic kinase signalling, proliferation and mitosis, as well as cell invasion and metastasis.
TL;DR: Hox genes, a highly conserved subgroup of the homeobox superfamily, have crucial roles in development, regulating numerous processes including apoptosis, receptor signalling, differentiation, motility and angiogenesis, and could be important in diagnosis and therapy.
Abstract: Hox genes, a highly conserved subgroup of the homeobox superfamily, have crucial roles in development, regulating numerous processes including apoptosis, receptor signalling, differentiation, motility and angiogenesis. Aberrations in Hox gene expression have been reported in abnormal development and malignancy, indicating that altered expression of Hox genes could be important for both oncogenesis and tumour suppression, depending on context. Therefore, Hox gene expression could be important in diagnosis and therapy.
TL;DR: This Review assesses the association of GEFs and GAPs with cancer and their druggability for cancer therapeutics.
Abstract: There is now considerable and increasing evidence for a causal role for aberrant activity of the Ras superfamily of small GTPases in human cancers. These GTPases function as GDP-GTP-regulated binary switches that control many fundamental cellular processes. A common mechanism of GTPase deregulation in cancer is the deregulated expression and/or activity of their regulatory proteins, guanine nucleotide exchange factors (GEFs) that promote formation of the active GTP-bound state and GTPase-activating proteins (GAPs) that return the GTPase to its GDP-bound inactive state. In this Review, we assess the association of GEFs and GAPs with cancer and their druggability for cancer therapeutics.
TL;DR: The epidemiology of KS and KSHV is described, and the insights into the remarkable mechanisms through which K SHV can induce KS that have been gained in the past 16 years are described.
Abstract: Kaposi's sarcoma (KS) is the most common cancer in HIV-infected untreated individuals. Kaposi's sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus 8 (HHV8)) is the infectious cause of this neoplasm. In this Review we describe the epidemiology of KS and KSHV, and the insights into the remarkable mechanisms through which KSHV can induce KS that have been gained in the past 16 years. KSHV latent transcripts, such as latency-associated nuclear antigen (LANA), viral cyclin, viral FLIP and viral-encoded microRNAs, drive cell proliferation and prevent apoptosis, whereas KSHV lytic proteins, such as viral G protein-coupled receptor, K1 and virally encoded cytokines (viral interleukin-6 and viral chemokines) further contribute to the unique angioproliferative and inflammatory KS lesions through a mechanism called paracrine neoplasia.
TL;DR: Developments in the understanding of malignant brain tumours in the context of the evolving notion of molecular pathology are summarized and the implications that this work has on the design of new treatment regimens are discussed.
Abstract: Malignant brain tumours continue to be the cause of a disproportionate level of morbidity and mortality across a wide range of individuals. The most common variants in the adult and paediatric populations - malignant glioma and medulloblastoma, respectively - have been the subject of increasingly intensive research over the past two decades that has led to considerable advances in the understanding of their basic biology and pathogenesis. This Review summarizes these developments in the context of the evolving notion of molecular pathology and discusses the implications that this work has on the design of new treatment regimens.
TL;DR: In this Opinion article, the parallels and differences in the angiogenic process under either a physiological or a pathological state, especially tumorigenesis are discussed.
Abstract: The cardiovascular system ensures the delivery of nutrients, oxygen, and blood and immune cells to all organs and tissues: it is also responsible for the removal of waste metabolites. The vascular system develops and matures through two tightly regulated processes: vasculogenesis and angiogenesis. Angiogenesis is active only under specific physiological conditions in healthy adults but the vasculature can be aberrantly activated to generate new blood vessels during pathological conditions such as cancer and chronic inflammation. In this Opinion article we discuss the parallels and differences in the angiogenic process under either a physiological or a pathological state, especially tumorigenesis.
TL;DR: In this Opinion article, some of the strategies that are currently being used to identify new therapeutic combinations of kinase targets are discussed.
Abstract: Kinase inhibitors are the largest class of new cancer drugs. However, it is already apparent that most tumours can escape from the inhibition of any single kinase. If it is necessary to inhibit multiple kinases, how do we choose which ones? In this Opinion article, we discuss some of the strategies that are currently being used to identify new therapeutic combinations of kinase targets.
TL;DR: It is proposed that synthetic biology techniques can be used to solve many of the key challenges that are associated with bacterial therapies, such as toxicity, stability and efficiency, and can been used to tune their beneficial features, allowing the engineering of 'perfect' cancer therapies.
Abstract: Bacterial therapies possess many unique mechanisms for treating cancer that are unachievable with standard methods. Bacteria can specifically target tumors, actively penetrate tissue, are easily detected and can controllably induce cytotoxicity. Over that last decade, Salmonella, Clostridium and other genera have been shown to control tumor growth and promote survival in animal models. In this Innovation article I propose that synthetic biology techniques can be used to solve many of the key challenges associated with bacterial therapies such as toxicity, stability and efficiency; and can be used to tune their beneficial features, allowing the engineering of ‘perfect’ cancer therapies.
TL;DR: Efforts to discover new cancer drugs and predict their clinical activity are limited by the fact that laboratory models to test drug efficacy do not faithfully recapitulate this complex disease.
Abstract: Efforts to discover new cancer drugs and predict their clinical activity are limited by the fact that laboratory models to test drug efficacy do not faithfully recapitulate this complex disease. One important model system for evaluating candidate anticancer agents is human tumour-derived cell lines. Although cultured cancer cells can exhibit distinct properties compared with their naturally growing counterparts, recent technologies that facilitate the parallel analysis of large panels of such lines, together with genomic technologies that define their genetic constitution, have revitalized efforts to use cancer cell lines to assess the clinical utility of new investigational cancer drugs and to discover predictive biomarkers.
TL;DR: A diverse group of viruses reveals unexpected connections between innate immunity, immune sensors and tumour suppressor signalling that control both viral infection and cancer.
Abstract: The year 2011 marks the centenary of Francis Peyton Rous's landmark experiments on an avian cancer virus. Since then, seven human viruses have been found to cause 10-15% of human cancers worldwide. Viruses have been central to modern cancer research and provide profound insights into both infectious and non-infectious cancer causes. This diverse group of viruses reveals unexpected connections between innate immunity, immune sensors and tumour suppressor signalling that control both viral infection and cancer. This Timeline article describes common features of human tumour viruses and discusses how new technologies can be used to identify infectious causes of cancer.