Showing papers in "Nature Reviews Cancer in 2009"
TL;DR: Signal transducer and activator of transcription proteins are central in determining whether immune responses in the tumour microenvironment promote or inhibit cancer, and STAT3 is a promising target to redirect inflammation for cancer therapy.
Abstract: Commensurate with their roles in regulating cytokine-dependent inflammation and immunity, signal transducer and activator of transcription (STAT) proteins are central in determining whether immune responses in the tumour microenvironment promote or inhibit cancer. Persistently activated STAT3 and, to some extent, STAT5 increase tumour cell proliferation, survival and invasion while suppressing anti-tumour immunity. The persistent activation of STAT3 also mediates tumour-promoting inflammation. STAT3 has this dual role in tumour inflammation and immunity by promoting pro-oncogenic inflammatory pathways, including nuclear factor-kappaB (NF-kappaB) and interleukin-6 (IL-6)-GP130-Janus kinase (JAK) pathways, and by opposing STAT1- and NF-kappaB-mediated T helper 1 anti-tumour immune responses. Consequently, STAT3 is a promising target to redirect inflammation for cancer therapy.
3,564 citations
TL;DR: Experimental data demonstrating the role of the microenvironment in metastasis is described, areas for future research are identified and possible new therapeutic avenues are suggested.
Abstract: Metastasis is a multistage process that requires cancer cells to escape from the primary tumour, survive in the circulation, seed at distant sites and grow. Each of these processes involves rate-limiting steps that are influenced by non-malignant cells of the tumour microenvironment. Many of these cells are derived from the bone marrow, particularly the myeloid lineage, and are recruited by cancer cells to enhance their survival, growth, invasion and dissemination. This Review describes experimental data demonstrating the role of the microenvironment in metastasis, identifies areas for future research and suggests possible new therapeutic avenues.
3,332 citations
TL;DR: Genetic evidence suggests that tumour cells may also require specific interphase CDKs for proliferation, and selective CDK inhibition may provide therapeutic benefit against certain human neoplasias.
Abstract: Tumour-associated cell cycle defects are often mediated by alterations in cyclin-dependent kinase (CDK) activity. Misregulated CDKs induce unscheduled proliferation as well as genomic and chromosomal instability. According to current models, mammalian CDKs are essential for driving each cell cycle phase, so therapeutic strategies that block CDK activity are unlikely to selectively target tumour cells. However, recent genetic evidence has revealed that, whereas CDK1 is required for the cell cycle, interphase CDKs are only essential for proliferation of specialized cells. Emerging evidence suggests that tumour cells may also require specific interphase CDKs for proliferation. Thus, selective CDK inhibition may provide therapeutic benefit against certain human neoplasias.
3,146 citations
TL;DR: Owing to the importance of these tumour-associated phenotypes in metastasis and cancer-related mortality, targeting the products of such cellular plasticity is an attractive but challenging approach that is likely to lead to improved clinical management of cancer patients.
Abstract: Transitions between epithelial and mesenchymal states have crucial roles in embryonic development. Emerging data suggest a role for these processes in regulating cellular plasticity in normal adult tissues and in tumours, where they can generate multiple, distinct cellular subpopulations contributing to intratumoural heterogeneity. Some of these subpopulations may exhibit more differentiated features, whereas others have characteristics of stem cells. Owing to the importance of these tumour-associated phenotypes in metastasis and cancer-related mortality, targeting the products of such cellular plasticity is an attractive but challenging approach that is likely to lead to improved clinical management of cancer patients.
3,101 citations
TL;DR: This Review provides a broad overview of some of the approaches currently used to discover and characterize new kinase inhibitors, and discusses the current challenges in the field.
Abstract: Deregulation of kinase activity has emerged as a major mechanism by which cancer cells evade normal physiological constraints on growth and survival. To date, 11 kinase inhibitors have received US Food and Drug Administration approval as cancer treatments, and there are considerable efforts to develop selective small molecule inhibitors for a host of other kinases that are implicated in cancer and other diseases. Herein we discuss the current challenges in the field, such as designing selective inhibitors and developing strategies to overcome resistance mutations. This Review provides a broad overview of some of the approaches currently used to discover and characterize new kinase inhibitors.
2,420 citations
TL;DR: Striking disparities in the natural progression of different cancers raise important questions about the evolution of metastatic traits, the genetic determinants of these properties and the mechanisms that lead to the selection of metastasis cells.
Abstract: Metastasis to distant organs is an ominous feature of most malignant tumours but the natural history of this process varies in different cancers. The cellular origin, intrinsic properties of the tumour, tissue affinities and circulation patterns determine not only the sites of tumour spread, but also the temporal course and severity of metastasis to vital organs. Striking disparities in the natural progression of different cancers raise important questions about the evolution of metastatic traits, the genetic determinants of these properties and the mechanisms that lead to the selection of metastatic cells.
2,403 citations
TL;DR: The therapeutic potential of drugs targeting PI3K–Akt signalling for the treatment of cancer is discussed and the advantages and drawbacks of different treatment strategies for targeting this pathway are focused on.
Abstract: There are ample genetic and laboratory studies that suggest the PI3K-Akt pathway is vital to the growth and survival of cancer cells. Inhibitors targeting this pathway are entering the clinic at a rapid pace. In this Review, the therapeutic potential of drugs targeting PI3K-Akt signalling for the treatment of cancer is discussed. I focus on the advantages and drawbacks of different treatment strategies for targeting this pathway, the cancers that might respond best to these therapies and the challenges and limitations that confront their clinical development.
2,277 citations
TL;DR: This Review focuses on recent advances in the understanding of the regulation of p21 and its biological functions with emphasis on its p53-independent tumour suppressor activities and paradoxical tumour-promoting activities, and their implications in cancer.
Abstract: One of the main engines that drives cellular transformation is the loss of proper control of the mammalian cell cycle. The cyclin-dependent kinase inhibitor p21 (also known as p21WAF1/Cip1) promotes cell cycle arrest in response to many stimuli. It is well positioned to function as both a sensor and an effector of multiple anti-proliferative signals. This Review focuses on recent advances in our understanding of the regulation of p21 and its biological functions with emphasis on its p53-independent tumour suppressor activities and paradoxical tumour-promoting activities, and their implications in cancer.
2,247 citations
TL;DR: This Review highlights the recent progress made in defining the functions of the JNK and p38 MAPK pathways in different cancers.
Abstract: Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) family members function in a cell context-specific and cell type-specific manner to integrate signals that affect proliferation, differentiation, survival and migration. Consistent with the importance of these events in tumorigenesis, JNK and p38 MAPK signalling is associated with cancers in humans and mice. Studies in mouse models have been essential to better understand how these MAPKs control cancer development, and these models are expected to provide new strategies for the design of improved therapeutic approaches. In this Review we highlight the recent progress made in defining the functions of the JNK and p38 MAPK pathways in different cancers.
2,164 citations
TL;DR: The changing force that cells experience needs to be considered when trying to understand the complex nature of tumorigenesis.
Abstract: Cells within tissues are continuously exposed to physical forces including hydrostatic pressure, shear stress, and compression and tension forces. Cells dynamically adapt to force by modifying their behaviour and remodelling their microenvironment. They also sense these forces through mechanoreceptors and respond by exerting reciprocal actomyosin- and cytoskeletal-dependent cell-generated force by a process termed 'mechanoreciprocity'. Loss of mechanoreciprocity has been shown to promote the progression of disease, including cancer. Moreover, the mechanical properties of a tissue contribute to disease progression, compromise treatment and might also alter cancer risk. Thus, the changing force that cells experience needs to be considered when trying to understand the complex nature of tumorigenesis.
1,706 citations
TL;DR: Now that links between inflammation and cancer are appreciated, is TNF a target or a therapeutic in malignant disease — or both?
Abstract: Tumour necrosis factor (TNF) is a major inflammatory cytokine that was first identified for its ability to induce rapid haemorrhagic necrosis of experimental cancers. When efforts to harness this anti-tumour activity in cancer treatments were underway, a paradoxical tumour-promoting role of TNF became apparent. Now that links between inflammation and cancer are appreciated, is TNF a target or a therapeutic in malignant disease -- or both?
TL;DR: The connection of AMPK with several tumour suppressors suggests that therapeutic manipulation of this pathway using established diabetes drugs warrants further investigation in patients with cancer.
Abstract: In the past decade, studies of the human tumour suppressor LKB1 have uncovered a novel signalling pathway that links cell metabolism to growth control and cell polarity. LKB1 encodes a serine-threonine kinase that directly phosphorylates and activates AMPK, a central metabolic sensor. AMPK regulates lipid, cholesterol and glucose metabolism in specialized metabolic tissues, such as liver, muscle and adipose tissue. This function has made AMPK a key therapeutic target in patients with diabetes. The connection of AMPK with several tumour suppressors suggests that therapeutic manipulation of this pathway using established diabetes drugs warrants further investigation in patients with cancer.
TL;DR: Thirty years ago p53 was discovered as a cellular partner of simian virus 40 large T-antigen, the oncoprotein of this tumour virus, and new functions of this protein were revealed, including the regulation of metabolic pathways and cytokines that are required for embryo implantation.
Abstract: When p53 was first discovered, it received relatively little attention from cancer researchers The road leading to p53's rise to fame, and the recognition ofTP53as the most frequently altered gene in human cancer, has been long and winding This Timeline examines the rich history of this pivotal tumour suppressor Thirty years ago p53 was discovered as a cellular partner of simian virus 40 large T-antigen, the oncoprotein of this tumour virus The first decade of p53 research saw the cloning of p53 DNA and the realization that p53 is not an oncogene but a tumour suppressor that is very frequently mutated in human cancer In the second decade of research, the function of p53 was uncovered: it is a transcription factor induced by stress, which can promote cell cycle arrest, apoptosis and senescence In the third decade after its discovery new functions of this protein were revealed, including the regulation of metabolic pathways and cytokines that are required for embryo implantation The fourth decade of research may see new p53-based drugs to treat cancer What is next is anybody's guess
TL;DR: These studies promise refined targeting of TOP2 as an effective anticancer strategy and the ability to interfere with TOP2 and generate enzyme-mediated DNA damage is an effective strategy for cancer chemotherapy.
Abstract: Recent molecular studies have expanded the biological contexts in which topoisomerase II (TOP2) has crucial functions, including DNA replication, transcription and chromosome segregation. Although the biological functions of TOP2 are important for ensuring genomic integrity, the ability to interfere with TOP2 and generate enzyme-mediated DNA damage is an effective strategy for cancer chemotherapy. The molecular tools that have allowed an understanding of the biological functions of TOP2 are also being applied to understanding the details of drug action. These studies promise refined targeting of TOP2 as an effective anticancer strategy.
TL;DR: Increase in long-term survival in ovarian cancer patients might be achieved by translating recent insights at the molecular and cellular levels to personalize individual strategies for treatment and to optimize early detection.
Abstract: Over the past two decades, the 5-year survival for ovarian cancer patients has substantially improved owing to more effective surgery and treatment with empirically optimized combinations of cytotoxic drugs, but the overall cure rate remains approximately 30%. Many investigators think that further empirical trials using combinations of conventional agents are likely to produce only modest incremental improvements in outcome. Given the heterogeneity of this disease, increases in long-term survival might be achieved by translating recent insights at the molecular and cellular levels to personalize individual strategies for treatment and to optimize early detection.
TL;DR: The development of large-scale computational and genetic approaches offers the promise of identifying the mediators of endocrine resistance that may be exploited as potential therapeutic targets and biomarkers of response in the clinic.
Abstract: The efficacy of endocrine therapies (such as tamoxifen) in breast cancer is limited by intrinsic and acquired therapeutic resistance. What do we know about the genetic lesions and molecular processes that determine endocrine resistance in the clinic, and how can we use this to improve therapy? Endocrine therapies targeting oestrogen action (anti-oestrogens, such as tamoxifen, and aromatase inhibitors) decrease mortality from breast cancer, but their efficacy is limited by intrinsic and acquired therapeutic resistance. Candidate molecular biomarkers and gene expression signatures of tamoxifen response emphasize the importance of deregulation of proliferation and survival signalling in endocrine resistance. However, definition of the specific genetic lesions and molecular processes that determine clinical endocrine resistance is incomplete. The development of large-scale computational and genetic approaches offers the promise of identifying the mediators of endocrine resistance that may be exploited as potential therapeutic targets and biomarkers of response in the clinic.
TL;DR: The findings that certain transmembrane mucins induce transformation and promote tumour progression have provided the experimental basis for demonstrating that inhibitors of their function are effective as anti-tumour agents in preclinical models.
Abstract: Epithelia are protected from adverse conditions by a mucous barrier. The secreted and transmembrane mucins that constitute the mucous barrier are largely unrecognized as effectors of carcinogenesis. However, both types of mucins are intimately involved in inflammation and cancer. Moreover, diverse human malignancies overexpress transmembrane mucins to exploit their role in signalling cell growth and survival. Mucins have thus been identified as markers of adverse prognosis and as attractive therapeutic targets. Notably, the findings that certain transmembrane mucins induce transformation and promote tumour progression have provided the experimental basis for demonstrating that inhibitors of their function are effective as anti-tumour agents in preclinical models.
TL;DR: Emerging data that support the 'seed and soil' hypothesis for metastasis are presented and the potential mechanism and temporal sequence by which changes occur in tissues distant from the primary tumour are outlined.
Abstract: The 'seed and soil' hypothesis for metastasis sets forth the concept that a conducive microenvironment, or niche, is required for disseminating tumour cells to engraft distant sites. This Opinion presents emerging data that support this concept and outlines the potential mechanism and temporal sequence by which changes occur in tissues distant from the primary tumour. To enable improvements in the prognosis of advanced malignancy, early interventions that target both the disseminating seed and the metastatic soil are likely to be required.
TL;DR: The role of two important family members of the epidermal growth factor receptor (Erbb) family is re-evaluate, the mechanisms of action are explored and preclinical and clinical data for new therapies that target signalling through these pivotal receptors are explored.
Abstract: Aberrant receptor expression or functioning of the epidermal growth factor receptor (Erbb) family plays a crucial part in the development and evolution of cancer. Inhibiting the signalling activity of individual receptors in this family has advanced the treatment of a range of human cancers. In this Review we re-evaluate the role of two important family members, ERBB2 (also known as HER2) and ERBB3 (also known as HER3), and explore the mechanisms of action and preclinical and clinical data for new therapies that target signalling through these pivotal receptors. These new therapies include tyrosine kinase inhibitors, antibody-chemotherapy conjugates, heat-shock protein inhibitors and antibodies that interfere with the formation of ERBB2-ERBB3 dimers.
TL;DR: This Perspective draws together data from disease courses, tumour growth rates, autopsy studies, clinical trials and molecular genetic analyses of primary and disseminated tumour cells in support of the parallel progression model.
Abstract: Systemic cancer progression is accounted for in two basic models. The prevailing archetype places the engine of cancer progression within the primary tumour before metastatic dissemination of fully malignant cells. The second posits parallel, independent progression of metastases arising from early disseminated tumour cells. This Perspective draws together data from disease courses, tumour growth rates, autopsy studies, clinical trials and molecular genetic analyses of primary and disseminated tumour cells in support of the parallel progression model. Consideration of this model urges review of current diagnostic and therapeutic routines.
TL;DR: Recent studies on mutant p53 regulation, gain-of-function mechanisms, transcriptional effects and prognostic association are reviewed, with a focus on the clinical implications of these findings.
Abstract: Ample data indicate that mutant p53 proteins not only lose their tumour suppressive functions, but also gain new abilities that promote tumorigenesis. Moreover, recent studies have modified our view of mutant p53 proteins, portraying them not as inert mutants, but rather as regulated proteins that influence the cancer cell transcriptome and phenotype. This influence is clinically manifested as association of TP53 mutations with poor prognosis and drug resistance in a growing array of malignancies. Here, we review recent studies on mutant p53 regulation, gain-of-function mechanisms, transcriptional effects and prognostic association, with a focus on the clinical implications of these findings.
TL;DR: There is considerable evidence that tea polyphenols, in particular (−)-epigallocatechin-3-gallate, inhibit enzyme activities and signal transduction pathways, resulting in the suppression of cell proliferation and enhancement of apoptosis, as well as the inhibition of cell invasion, angiogenesis and metastasis.
Abstract: Extracts of tea, especially green tea, and tea polyphenols have been shown to inhibit the formation and development of tumours at different organ sites in animal models. There is considerable evidence that tea polyphenols, in particular (-)-epigallocatechin-3-gallate, inhibit enzyme activities and signal transduction pathways, resulting in the suppression of cell proliferation and enhancement of apoptosis, as well as the inhibition of cell invasion,angiogenesis and metastasis. Here, we review these biological activities and existing data relating tea consumption to human cancer risk in an attempt to understand the potential use of tea for cancer prevention.
[...]
TL;DR: The p53 gene has been shown to respond to metabolic changes and to influence metabolic pathways through several mechanisms that reflect the function of basal p53 levels that do not require overt activation and others might even promote, rather than inhibit, tumour progression.
Abstract: Although metabolic alterations have been observed in cancer for almost a century, only recently have the mechanisms underlying these changes been identified and the importance of metabolic transformation realized p53 has been shown to respond to metabolic changes and to influence metabolic pathways through several mechanisms The contributions of these activities to tumour suppression are complex and potentially rather surprising: some reflect the function of basal p53 levels that do not require overt activation and others might even promote, rather than inhibit, tumour progression
TL;DR: It is proposed that there are alternative tumour-promoting activities for the E2F family, which are independent of cell cycle regulation.
Abstract: Mutations of the retinoblastoma tumour suppressor gene (RB1) or components regulating the RB pathway have been identified in almost every human malignancy. The E2F transcription factors function in cell cycle control and are intimately regulated by RB. Studies of model organisms have revealed conserved functions for E2Fs during development, suggesting that the cancer-related proliferative roles of E2F family members represent a recent evolutionary adaptation. However, given that some human tumours have concurrent RB1 inactivation and E2F amplification and overexpression, we propose that there are alternative tumour-promoting activities for the E2F family, which are independent of cell cycle regulation.
TL;DR: How the function of TLRs may relate to these processes in the context of carcinogenesis is discussed.
Abstract: Toll-like receptors (TLRs) are a family of pattern recognition receptors that are best-known for their role in host defence from infection. Emerging evidence also suggests that TLRs have an important role in maintaining tissue homeostasis by regulating the inflammatory and tissue repair responses to injury. The development of cancer has been associated with microbial infection, injury, inflammation and tissue repair. Here we discuss how the function of TLRs may relate to these processes in the context of carcinogenesis.
TL;DR: Several original approaches to drug discovery that could have wide applications to drug development are being used, including molecules that activate p53 by blocking protein–protein interactions with MDM2 and p53-binding molecules that can rescue the function of certain p53 mutants.
Abstract: Currently, around 11 million people are living with a tumour that contains an inactivating mutation of TP53 (the human gene that encodes p53) and another 11 million have tumours in which the p53 pathway is partially abrogated through the inactivation of other signalling or effector components. The p53 pathway is therefore a prime target for new cancer drug development, and several original approaches to drug discovery that could have wide applications to drug development are being used. In one approach, molecules that activate p53 by blocking protein-protein interactions with MDM2 are in early clinical development. Remarkable progress has also been made in the development of p53-binding molecules that can rescue the function of certain p53 mutants. Finally, cell-based assays are being used to discover compounds that exploit the p53 pathway by either seeking targets and compounds that show synthetic lethality with TP53 mutations or by looking for non-genotoxic activators of the p53 response.
TL;DR: Recently emerging evidence points to a crucial role in oncogene-induced cellular senescence for the 'senescence-messaging secretome' or SMS, setting the stage for cross-talk between senescent cells and their environment.
Abstract: Oncogene-induced cellular senescence constitutes a strong anti-proliferative response, which can be set in motion following either oncogene activation or loss of tumour suppressor signalling. It serves to limit the expansion of early neoplastic cells and as such is a potent cancer-protective response to oncogenic events. Recently emerging evidence points to a crucial role in oncogene-induced cellular senescence for the 'senescence-messaging secretome' or SMS, setting the stage for cross-talk between senescent cells and their environment. How are such signals integrated into a coordinated response and what are the implications of this unexpected finding?
TL;DR: It is proposed that new therapeutic strategies targeting this interaction between tumour cells and the surrounding microenvironment should be applied during initial treatment to prevent the emergence of acquired resistance.
Abstract: Environment-mediated drug resistance is a form of de novo drug resistance that protects tumour cells from the initial effects of diverse therapies. Surviving foci of residual disease can then develop complex and permanent acquired resistance in response to the selective pressure of therapy. Recent evidence indicates that environment-mediated drug resistance arises from an adaptive, reciprocal signalling dialogue between tumour cells and the surrounding microenvironment. We propose that new therapeutic strategies targeting this interaction should be applied during initial treatment to prevent the emergence of acquired resistance.
TL;DR: The concept that the same miRNAs could be involved both in the cancer stem cell phenotype and in the ability of specific cancer cells to produce metastases, thus representing a mechanistic link between the initial and the final steps of tumorigenesis is developed.
Abstract: microRNAs have recently been shown to affect diverse processes involved in metastasis. How do microRNAs interfere with or promote metastasis, could they be used as predictive markers, and are they possible therapeutic targets?
TL;DR: How the field of apoptosis biology has developed in the context of its contribution to the authors' understanding of cell death, or lack of it, in the development of malignant disease is focused on.
Abstract: In multicellular organisms, the total number of cells is a balance between the cell-generating effects of mitosis and cell death that is induced through apoptosis. A disruption of this delicate balance can lead to the development of cancer. This Timeline article focuses on how the field of apoptosis biology has developed in the context of its contribution to our understanding of cell death, or lack of it, in the development of malignant disease. It traces the course of research from key discoveries in fundamental biology to potential therapeutic applications.