Showing papers in "Nature Reviews Cancer in 2014"
TL;DR: Well known for its role in tumour cell proliferation, survival, invasion and immunosuppression, JAK–STAT3 signalling also promotes cancer through inflammation, obesity, stem cells and the pre-metastatic niche.
Abstract: The Janus kinases (JAKs) and signal transducer and activator of transcription (STAT) proteins, particularly STAT3, are among the most promising new targets for cancer therapy. In addition to interleukin-6 (IL-6) and its family members, multiple pathways, including G-protein-coupled receptors (GPCRs), Toll-like receptors (TLRs) and microRNAs were recently identified to regulate JAK-STAT signalling in cancer. Well known for its role in tumour cell proliferation, survival, invasion and immunosuppression, JAK-STAT3 signalling also promotes cancer through inflammation, obesity, stem cells and the pre-metastatic niche. In addition to its established role as a transcription factor in cancer, STAT3 regulates mitochondrion functions, as well as gene expression through epigenetic mechanisms. Newly identified regulators and functions of JAK-STAT3 in tumours are important targets for potential therapeutic strategies in the treatment of cancer.
1,572 citations
TL;DR: The mechanisms of tumour cell death that are induced by the most common thermoablative techniques are examined and the rapidly developing areas of research in the field are discussed, including combinatorial ablation and immunotherapy, synergy with conventional chemotherapy and radiation, and the development of a new ablation modality in irreversible electroporation.
Abstract: Minimally invasive thermal ablation of tumours has become common since the advent of modern imaging. From the ablation of small, unresectable tumours to experimental therapies, percutaneous radiofrequency ablation, microwave ablation, cryoablation and irreversible electroporation have an increasing role in the treatment of solid neoplasms. This Opinion article examines the mechanisms of tumour cell death that are induced by the most common thermoablative techniques and discusses the rapidly developing areas of research in the field, including combinatorial ablation and immunotherapy, synergy with conventional chemotherapy and radiation, and the development of a new ablation modality in irreversible electroporation.
1,354 citations
TL;DR: An impressive list of potential therapeutic targets was unveiled, drastically altering the clinical evaluation and treatment of patients for non-small-cell lung cancers, including immunotherapy.
Abstract: Non-small-cell lung cancers (NSCLCs), the most common lung cancers, are known to have diverse pathological features. During the past decade, in-depth analyses of lung cancer genomes and signalling pathways have further defined NSCLCs as a group of distinct diseases with genetic and cellular heterogeneity. Consequently, an impressive list of potential therapeutic targets was unveiled, drastically altering the clinical evaluation and treatment of patients. Many targeted therapies have been developed with compelling clinical proofs of concept; however, treatment responses are typically short-lived. Further studies of the tumour microenvironment have uncovered new possible avenues to control this deadly disease, including immunotherapy.
1,189 citations
TL;DR: The targeted disruption of mitochondria-to-cell redox communication represents a promising avenue for future therapy for cancer treatment.
Abstract: Mitochondria cooperate with their host cells by contributing to bioenergetics, metabolism, biosynthesis, and cell death or survival functions. Reactive oxygen species (ROS) generated by mitochondria participate in stress signalling in normal cells but also contribute to the initiation of nuclear or mitochondrial DNA mutations that promote neoplastic transformation. In cancer cells, mitochondrial ROS amplify the tumorigenic phenotype and accelerate the accumulation of additional mutations that lead to metastatic behaviour. As mitochondria carry out important functions in normal cells, disabling their function is not a feasible therapy for cancer. However, ROS signalling contributes to proliferation and survival in many cancers, so the targeted disruption of mitochondria-to-cell redox communication represents a promising avenue for future therapy.
1,188 citations
TL;DR: The roles of classical p53 functions, as well as emerging p53-regulated processes, in tumour suppression are discussed.
Abstract: p53 is a crucial tumour suppressor that responds to diverse stress signals by orchestrating specific cellular responses, including transient cell cycle arrest, cellular senescence and apoptosis, which are all processes associated with tumour suppression. However, recent studies have challenged the relative importance of these canonical cellular responses for p53-mediated tumour suppression and have highlighted roles for p53 in modulating other cellular processes, including metabolism, stem cell maintenance, invasion and metastasis, as well as communication within the tumour microenvironment. In this Opinion article, we discuss the roles of classical p53 functions, as well as emerging p53-regulated processes, in tumour suppression.
1,084 citations
TL;DR: A conceptual framework of CTC assays is proposed and current challenges of C TC research are pointed out, which might structure this dynamic field of translational cancer research.
Abstract: Circulating tumour cells (CTCs) are the subject of many published papers, but the diversity of assays used for their analysis can be daunting. This Opinion article discusses issues regarding the detection and characterization of CTCs, and poses the major outstanding questions in this field.
1,074 citations
TL;DR: A direct link between hypoxia and the composition and the organization of the ECM is established, which suggests a new model in which multiple microenvironmental signals might converge to synergistically influence metastatic outcome.
Abstract: Of the deaths attributed to cancer, 90% are due to metastasis, and treatments that prevent or cure metastasis remain elusive. Emerging data indicate that hypoxia and the extracellular matrix (ECM) might have crucial roles in metastasis. During tumour evolution, changes in the composition and the overall content of the ECM reflect both its biophysical and biological properties and these strongly influence tumour and stromal cell properties, such as proliferation and motility. Originally thought of as independent contributors to metastatic spread, recent studies have established a direct link between hypoxia and the composition and the organization of the ECM, which suggests a new model in which multiple microenvironmental signals might converge to synergistically influence metastatic outcome.
1,034 citations
TL;DR: Accumulating results from preclinical and some clinical studies strongly suggest that vitamin D deficiency increases the risk of developing cancer and that avoiding deficiency and adding vitamin D supplements might be an economical and safe way to reduce cancer incidence and improve cancer prognosis and outcome.
Abstract: Vitamin D is not really a vitamin but the precursor to the potent steroid hormone calcitriol, which has widespread actions throughout the body. Calcitriol regulates numerous cellular pathways that could have a role in determining cancer risk and prognosis. Although epidemiological and early clinical trials are inconsistent, and randomized control trials in humans do not yet exist to conclusively support a beneficial role for vitamin D, accumulating results from preclinical and some clinical studies strongly suggest that vitamin D deficiency increases the risk of developing cancer and that avoiding deficiency and adding vitamin D supplements might be an economical and safe way to reduce cancer incidence and improve cancer prognosis and outcome.
995 citations
TL;DR: Focal adhesion kinase signalling effects on both tumour and stromal cell biology that provide rationale and support for future therapeutic opportunities are discussed.
Abstract: Focal adhesion kinase (FAK) is a cytoplasmic protein tyrosine kinase that is overexpressed and activated in several advanced-stage solid cancers. FAK promotes tumour progression and metastasis through effects on cancer cells, as well as stromal cells of the tumour microenvironment. The kinase-dependent and kinase-independent functions of FAK control cell movement, invasion, survival, gene expression and cancer stem cell self-renewal. Small molecule FAK inhibitors decrease tumour growth and metastasis in several preclinical models and have initial clinical activity in patients with limited adverse events. In this Review, we discuss FAK signalling effects on both tumour and stromal cell biology that provide rationale and support for future therapeutic opportunities.
993 citations
TL;DR: The occurrence of cachexia in cancer patients is dependent on the patient response to tumour progression, including the activation of the inflammatory response and energetic inefficiency involving the mitochondria, and crosstalk between different cell types ultimately seems to result in muscle wasting.
Abstract: Cancer cachexia is a devastating, multifactorial and often irreversible syndrome that affects around 50-80% of cancer patients, depending on the tumour type, and that leads to substantial weight loss, primarily from loss of skeletal muscle and body fat. Since cachexia may account for up to 20% of cancer deaths, understanding the underlying molecular mechanisms is essential. The occurrence of cachexia in cancer patients is dependent on the patient response to tumour progression, including the activation of the inflammatory response and energetic inefficiency involving the mitochondria. Interestingly, crosstalk between different cell types ultimately seems to result in muscle wasting. Some of the recent progress in understanding the molecular mechanisms of cachexia may lead to new therapeutic approaches.
917 citations
TL;DR: The characteristics of tumour antigens that are recognized by spontaneous T cell responses in cancer patients and the paths that led to their identification are described.
Abstract: In this Timeline, we describe the characteristics of tumour antigens that are recognized by spontaneous T cell responses in cancer patients and the paths that led to their identification. We explain on what genetic basis most, but not all, of these antigens are tumour specific: that is, present on tumour cells but not on normal cells. We also discuss how strategies that target these tumour-specific antigens can lead either to tumour-specific or to crossreactive T cell responses, which is an issue that has important safety implications in immunotherapy. These safety issues are even more of a concern for strategies targeting antigens that are not known to induce spontaneous T cell responses in patients.
TL;DR: Analysis of approximately 7 years of literature reveals a growing focus on tumour and normal stem cell quiescence, extracellular and stromal microenvironments, autophagy and epigenetics as mechanisms that dictate tumour cell dormancy.
Abstract: Metastases arise from residual disseminated tumour cells (DTCs). This can happen years after primary tumour treatment because residual tumour cells can enter dormancy and evade therapies. As the biology of minimal residual disease seems to diverge from that of proliferative lesions, understanding the underpinnings of this new cancer biology is key to prevent metastasis. Analysis of approximately 7 years of literature reveals a growing focus on tumour and normal stem cell quiescence, extracellular and stromal microenvironments, autophagy and epigenetics as mechanisms that dictate tumour cell dormancy. In this Review, we attempt to integrate this information and highlight both the weaknesses and the strengths in the field to provide a framework to understand and target this crucial step in cancer progression.
TL;DR: The impact of ER stress and UPR activation on every aspect of cancer is summarized and outstanding questions for which answers will pave the way for therapeutics are discussed.
Abstract: The endoplasmic reticulum (ER) is an essential organelle in eukaryotic cells for the storage and regulated release of calcium and as the entrance to the secretory pathway. Protein misfolding in the ER causes accumulation of misfolded proteins (ER stress) and activation of the unfolded protein response (UPR), which has evolved to maintain a productive ER protein-folding environment. Both ER stress and UPR activation are documented in many different human cancers. In this Review, we summarize the impact of ER stress and UPR activation on every aspect of cancer and discuss outstanding questions for which answers will pave the way for therapeutics.
TL;DR: The success of the innate immune stimulant mifamurtide in the adjuvant treatment of non-metastatic osteosarcoma suggests that newer immune-based treatments, such as immune checkpoint inhibitors, may substantially improve disease outcome.
Abstract: For the past 30 years, improvements in the survival of patients with osteosarcoma have been mostly incremental. Despite evidence of genomic instability and a high frequency of chromothripsis and kataegis, osteosarcomas carry few recurrent targetable mutations, and trials of targeted agents have been generally disappointing. Bone has a highly specialized immune environment and many immune signalling pathways are important in bone homeostasis. The success of the innate immune stimulant mifamurtide in the adjuvant treatment of non-metastatic osteosarcoma suggests that newer immune-based treatments, such as immune checkpoint inhibitors, may substantially improve disease outcome.
TL;DR: This Review describes the development of BRAF inhibitors and the results that have emerged from their analysis in both the laboratory and the clinic and enumerates mechanisms of resistance to BRAF inhibition that have been characterized.
Abstract: The identification of mutationally activated BRAF in many cancers altered our conception of the part played by the RAF family of protein kinases in oncogenesis In this Review, we describe the development of BRAF inhibitors and the results that have emerged from their analysis in both the laboratory and the clinic We discuss the spectrum of RAF mutations in human cancer and the complex interplay between the tissue of origin and the response to RAF inhibition Finally, we enumerate mechanisms of resistance to BRAF inhibition that have been characterized and postulate how strategies of RAF pathway inhibition may be extended in scope to benefit not only the thousands of patients who are diagnosed annually with BRAF-mutated metastatic melanoma but also the larger patient population with malignancies harbouring mutationally activated RAF genes that are ineffectively treated with the current generation of BRAF kinase inhibitors
TL;DR: Studies of aggressive tumours and tumour cell lines show increased levels of AHR and constitutive localization of this receptor in the nucleus, which suggests that the AHR is chronically activated in tumours, thus facilitating tumour progression.
Abstract: The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that is best known for mediating the toxicity and tumour-promoting properties of the carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin, commonly referred to as ‘dioxin’. AHR influences the major stages of tumorigenesis — initiation, promotion, progression and metastasis — and physiologically relevant AHR ligands are often formed during disease states or during heightened innate and adaptive immune responses. Interestingly, ligand specificity and affinity vary between rodents and humans. Studies of aggressive tumours and tumour cell lines show increased levels of AHR and constitutive localization of this receptor in the nucleus. This suggests that the AHR is chronically activated in tumours, thus facilitating tumour progression. This Review discusses the role of AHR in tumorigenesis and the potential for therapeutic modulation of its activity in tumours.
TL;DR: The burden of responsibility to understand the long-term morbidity and mortality that is associated with currently successful treatments must be borne by many, including the research and health care communities, survivor advocacy groups, and governmental and policy-making entities.
Abstract: Survival rates for most paediatric cancers have improved at a remarkable pace over the past four decades. In developed countries, cure is now the probable outcome for most children and adolescents who are diagnosed with cancer: their 5-year survival rate approaches 80%. However, the vast majority of these cancer survivors will have at least one chronic health condition by 40 years of age. The burden of responsibility to understand the long-term morbidity and mortality that is associated with currently successful treatments must be borne by many, including the research and health care communities, survivor advocacy groups, and governmental and policy-making entities.
TL;DR: A greater understanding of the specific roles of distinct lymphatic vessel subtypes in cancer provides opportunities to improve diagnostic and therapeutic approaches that aim to restrict the progression of cancer.
Abstract: The generation of new lymphatic vessels through lymphangiogenesis and the remodelling of existing lymphatics are thought to be important steps in cancer metastasis. The past decade has been exciting in terms of research into the molecular and cellular biology of lymphatic vessels in cancer, and it has been shown that the molecular control of tumour lymphangiogenesis has similarities to that of tumour angiogenesis. Nevertheless, there are significant mechanistic differences between these biological processes. We are now developing a greater understanding of the specific roles of distinct lymphatic vessel subtypes in cancer, and this provides opportunities to improve diagnostic and therapeutic approaches that aim to restrict the progression of cancer.
TL;DR: In tumours, autocrine and paracrine ligands and apoptotic cells are abundant, which provide a survival signal to the tumour cell and favour an anti-inflammatory, immunosuppressive microenvironment, which could stimulate antitumour immunity, reduce tumours cell survival, enhance chemosensitivity and diminish metastatic potential.
Abstract: The TYRO3, AXL (also known as UFO) and MERTK (TAM) family of receptor tyrosine kinases (RTKs) are aberrantly expressed in multiple haematological and epithelial malignancies. Rather than functioning as oncogenic drivers, their induction in tumour cells predominately promotes survival, chemoresistance and motility. The unique mode of maximal activation of this RTK family requires an extracellular lipid–protein complex. For example, the protein ligand, growth arrest-specific protein 6 (GAS6), binds to phosphatidylserine (PtdSer) that is externalized on apoptotic cell membranes, which activates MERTK on macrophages. This triggers engulfment of apoptotic material and subsequent anti-inflammatory macrophage polarization. In tumours, autocrine and paracrine ligands and apoptotic cells are abundant, which provide a survival signal to the tumour cell and favour an anti-inflammatory, immunosuppressive microenvironment. Thus, TAM kinase inhibition could stimulate antitumour immunity, reduce tumour cell survival, enhance chemosensitivity and diminish metastatic potential.
TL;DR: The ability to engineer OVs that express immune-stimulating 'cargo', the induction of immunogenic tumour cell death by OVs and the selective targeting of OVs to tumour beds suggests that they are the ideal reagents to enhance antitumour immune responses.
Abstract: Recent clinical data have emphatically shown the capacity of our immune systems to eradicate even advanced cancers. Although oncolytic viruses (OVs) were originally designed to function as tumour-lysing therapeutics, they have now been clinically shown to initiate systemic antitumour immune responses. Cell signalling pathways that are activated and promote the growth of tumour cells also favour the growth and replication of viruses within the cancer. The ability to engineer OVs that express immune-stimulating 'cargo', the induction of immunogenic tumour cell death by OVs and the selective targeting of OVs to tumour beds suggests that they are the ideal reagents to enhance antitumour immune responses. Coupling of OV therapy with tumour antigen vaccination, immune checkpoint inhibitors and adoptive cell therapy seems to be ready to converge towards a new generation of multimodal therapeutics to improve outcomes for cancer patients.
TL;DR: The glucose-regulated proteins are found and regulation are described, as well as their biological functions in cancer and promising agents that use or target the GRPs are developed, and their efficacy as anticancer therapeutics is discussed.
Abstract: The glucose-regulated proteins (GRPs) are stress-inducible chaperones that mostly reside in the endoplasmic reticulum or the mitochondria. Recent advances show that the GRPs have functions that are distinct from those of the related heat shock proteins, and they can be actively translocated to other cellular locations and assume novel functions that control signalling, proliferation, invasion, apoptosis, inflammation and immunity. Mouse models further identified their specific roles in development, tumorigenesis, metastasis and angiogenesis. This Review describes their discovery and regulation, as well as their biological functions in cancer. Promising agents that use or target the GRPs are being developed, and their efficacy as anticancer therapeutics is also discussed.
German Cancer Research Center1, Institut Gustave Roussy2, Duke University3, University of Toronto4, McGill University5, Institute of Cancer Research6, University of California, San Francisco7, Columbia University8, University of Texas MD Anderson Cancer Center9, Memorial Sloan Kettering Cancer Center10
TL;DR: The hallmark genetic alterations that are associated with distinct epigenetic features and patient characteristics in both paediatric and adult disease are summarized, and the complex interplay between the glioblastoma genome and epigenome is examined.
Abstract: We have extended our understanding of the molecular biology that underlies adult glioblastoma over many years. By contrast, high-grade gliomas in children and adolescents have remained a relatively under-investigated disease. The latest large-scale genomic and epigenomic profiling studies have yielded an unprecedented abundance of novel data and provided deeper insights into gliomagenesis across all age groups, which has highlighted key distinctions but also some commonalities. As we are on the verge of dissecting glioblastomas into meaningful biological subgroups, this Review summarizes the hallmark genetic alterations that are associated with distinct epigenetic features and patient characteristics in both paediatric and adult disease, and examines the complex interplay between the glioblastoma genome and epigenome.
TL;DR: Hereditary pheochromocytomas and paragangliomas are powerful models for recognizing cancer driver events, which can be harnessed for diagnostic purposes and for guiding the future development of targeted therapies.
Abstract: The neuroendocrine tumours pheochromocytomas and paragangliomas carry the highest degree of heritability in human neoplasms, enabling genetic alterations to be traced to clinical phenotypes through their transmission in families Mutations in more than a dozen distinct susceptibility genes have implicated multiple pathways in these tumours, offering insights into kinase downstream signalling interactions and hypoxia regulation, and uncovering links between metabolism, epigenetic remodelling and cell growth These advances extend to co-occurring tumours, including renal, thyroid and gastrointestinal malignancies Hereditary pheochromocytomas and paragangliomas are powerful models for recognizing cancer driver events, which can be harnessed for diagnostic purposes and for guiding the future development of targeted therapies
TL;DR: Intranuclear roles of IGFBPs in transcriptional regulation, induction of apoptosis and DNA damage repair point to their intimate involvement in tumour development, progression and resistance to treatment.
Abstract: The six members of the family of insulin-like growth factor (IGF) binding proteins (IGFBPs) were originally characterized as passive reservoirs of circulating IGFs, but they are now understood to have many actions beyond their endocrine role in IGF transport. IGFBPs also function in the pericellular and intracellular compartments to regulate cell growth and survival - they interact with many proteins, in addition to their canonical ligands IGF-I and IGF-II. Intranuclear roles of IGFBPs in transcriptional regulation, induction of apoptosis and DNA damage repair point to their intimate involvement in tumour development, progression and resistance to treatment. Tissue or circulating IGFBPs might also be useful as prognostic biomarkers.
TL;DR: The importance of BTK in various signalling pathways in the context of its therapeutic inhibition is highlighted and molecular effects that cannot be explained by the classic role ofBTK in BCR signalling are highlighted.
Abstract: Bruton's tyrosine kinase (BTK) is a key component of B cell receptor (BCR) signalling and functions as an important regulator of cell proliferation and cell survival in various B cell malignancies. Small-molecule inhibitors of BTK have shown antitumour activity in animal models and, recently, in clinical studies. High response rates were reported in patients with chronic lymphocytic leukaemia and mantle cell lymphoma. Remarkably, BTK inhibitors have molecular effects that cannot be explained by the classic role of BTK in BCR signalling. In this Review, we highlight the importance of BTK in various signalling pathways in the context of its therapeutic inhibition.
TL;DR: The complex roles of RET in homeostasis and survival of neural lineages and in tumour-associated inflammation might also suggest potential long-term pitfalls of broadly targeting RET.
Abstract: The RET receptor tyrosine kinase is crucial for normal development but also contributes to pathologies that reflect both the loss and the gain of RET function. Activation of RET occurs via oncogenic mutations in familial and sporadic cancers - most notably, those of the thyroid and the lung. RET has also recently been implicated in the progression of breast and pancreatic tumours, among others, which makes it an attractive target for small-molecule kinase inhibitors as therapeutics. However, the complex roles of RET in homeostasis and survival of neural lineages and in tumour-associated inflammation might also suggest potential long-term pitfalls of broadly targeting RET.
TL;DR: Additional genetic and mechanistic studies will help to define the role of each F-box protein in tumorigenesis, thereby paving the road for the rational design of F- box protein-targeted anticancer therapies.
Abstract: F-box proteins, which are the substrate-recognition subunits of SKP1–cullin 1–F-box protein (SCF) E3 ubiquitin ligase complexes, have pivotal roles in multiple cellular processes. This Review discusses how dysregulation of F-box protein-mediated proteolysis contributes to tumorigenesis.
TL;DR: The mechanisms of PAK activation in cancer, the key substrates that mediate the developmental and oncogenic effects of this family of kinases, and how small-molecule inhibitors of these enzymes might be best developed and deployed for the treatment of cancer are discussed.
Abstract: p21-Activated kinases (PAKs) are positioned at the nexus of several oncogenic signalling pathways. Overexpression or mutational activation of PAK isoforms frequently occurs in various human tumours, and recent data suggest that excessive PAK activity drives many of the cellular processes that are the hallmarks of cancer. In this Review, we discuss the mechanisms of PAK activation in cancer, the key substrates that mediate the developmental and oncogenic effects of this family of kinases, and how small-molecule inhibitors of these enzymes might be best developed and deployed for the treatment of cancer.
TL;DR: A fundamental understanding of interactions between tumour cells and non-malignant cells gives insight into the pathogenesis of most B cell lymphomas and identifies novel therapeutic opportunities for targeting oncogenic pathways, both now and in the future.
Abstract: B cell lymphomas are cancers that arise from cells that depend on numerous highly orchestrated interactions with immune and stromal cells in the course of normal development. Despite the recent focus on dissecting the genetic aberrations within cancer cells, it has been increasingly recognized that tumour cells retain a range of dependence on interactions with the non-malignant cells and stromal elements that constitute the tumour microenvironment. A fundamental understanding of these interactions gives insight into the pathogenesis of most B cell lymphomas and, moreover, identifies novel therapeutic opportunities for targeting oncogenic pathways, both now and in the future.
TL;DR: Senescence is now increasingly considered to be an integrated and widespread component that is potentially important for tumour development, tumour suppression and the response to therapy.
Abstract: The core aspect of the senescent phenotype is a stable state of cell cycle arrest. However, this is a disguise that conceals a highly active metabolic cell state with diverse functionality. Both the cell-autonomous and the non-cell-autonomous activities of senescent cells create spatiotemporally dynamic and context-dependent tissue reactions. For example, the senescence-associated secretory phenotype (SASP) provokes not only tumour-suppressive but also tumour-promoting responses. Senescence is now increasingly considered to be an integrated and widespread component that is potentially important for tumour development, tumour suppression and the response to therapy.