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Showing papers in "Nature Reviews Cancer in 2003"


Journal ArticleDOI
TL;DR: Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion.
Abstract: Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, glucose metabolism and invasion. Intratumoral hypoxia and genetic alterations can lead to HIF-1alpha overexpression, which has been associated with increased patient mortality in several cancer types. In preclinical studies, inhibition of HIF-1 activity has marked effects on tumour growth. Efforts are underway to identify inhibitors of HIF-1 and to test their efficacy as anticancer therapeutics.

6,024 citations


Journal ArticleDOI
TL;DR: PDT is being tested in the clinic for use in oncology — to treat cancers of the head and neck, brain, lung, pancreas, intraperitoneal cavity, breast, prostate and skin.
Abstract: The therapeutic properties of light have been known for thousands of years, but it was only in the last century that photodynamic therapy (PDT) was developed. At present, PDT is being tested in the clinic for use in oncology--to treat cancers of the head and neck, brain, lung, pancreas, intraperitoneal cavity, breast, prostate and skin. How does PDT work, and how can it be used to treat cancer and other diseases?

5,041 citations


Journal ArticleDOI
TL;DR: It is now known that the potential of a tumour cell to metastasize depends on its interactions with the homeostatic factors that promote tumour-cell growth, survival, angiogenesis, invasion and metastasis.
Abstract: Researchers have been studying metastasis for more than 100 years, and only recently have we gained insight into the mechanisms by which metastatic cells arise from primary tumours and the reasons that certain tumour types tend to metastasize to specific organs. Stephen Paget's 1889 proposal that metastasis depends on cross-talk between selected cancer cells (the 'seeds') and specific organ microenvironments (the 'soil') still holds forth today. It is now known that the potential of a tumour cell to metastasize depends on its interactions with the homeostatic factors that promote tumour-cell growth, survival, angiogenesis, invasion and metastasis. How has this field developed over the past century, and what major breakthroughs are most likely to lead to effective therapeutic approaches?

4,319 citations


Journal ArticleDOI
TL;DR: This work has shown that novel genes identified in DNA microarray profiling have the potential to identify novel genes that are involved in mediating resistance to 5-FU, and these genes might prove to be therapeutically valuable as new targets for chemotherapy, or as predictive biomarkers of response to5-FU-based chemotherapy.
Abstract: 5-fluorouracil (5-FU) is widely used in the treatment of cancer. Over the past 20 years, increased understanding of the mechanism of action of 5-FU has led to the development of strategies that increase its anticancer activity. Despite these advances, drug resistance remains a significant limitation to the clinical use of 5-FU. Emerging technologies, such as DNA microarray profiling, have the potential to identify novel genes that are involved in mediating resistance to 5-FU. Such target genes might prove to be therapeutically valuable as new targets for chemotherapy, or as predictive biomarkers of response to 5-FU-based chemotherapy.

4,177 citations


Journal ArticleDOI
TL;DR: The RAS proteins control signalling pathways that are key regulators of several aspects of normal cell growth and malignant transformation and are aberrant in most human tumours.
Abstract: The RAS proteins control signalling pathways that are key regulators of several aspects of normal cell growth and malignant transformation. They are aberrant in most human tumours due to activating mutations in the RAS genes themselves or to alterations in upstream or downstream signalling components. Rational therapies that target the RAS pathways might inhibit tumour growth, survival and spread. Several of these new therapeutic agents are showing promise in the clinic and many more are being developed.

3,105 citations


Journal ArticleDOI
TL;DR: Cancer cells possess a broad spectrum of migration and invasion mechanisms and learning more about the cellular and molecular basis of these different migration/invasion programmes will help to understand how cancer cells disseminate and lead to new treatment strategies.
Abstract: Cancer cells possess a broad spectrum of migration and invasion mechanisms. These include both individual and collective cell-migration strategies. Cancer therapeutics that are designed to target adhesion receptors or proteases have not proven to be effective in slowing tumour progression in clinical trials — this might be due to the fact that cancer cells can modify their migration mechanisms in response to different conditions. Learning more about the cellular and molecular basis of these different migration/invasion programmes will help us to understand how cancer cells disseminate and lead to new treatment strategies.

3,064 citations


Journal ArticleDOI
TL;DR: A more detailed understanding of the complex parameters that govern the interactions between the tumour and vascular compartments will help to improve anti-angiogenic strategies — not only for cancer treatment, but also for preventing recurrence.
Abstract: It has become evident that we cannot understand tumour growth without considering components of the stromal microenvironment, such as the vasculature. At the same time, the tumour phenotype determines the nature of the tumour vasculature. Much research is now devoted to determining the impact of angiogenesis on tumour development and progression, and the reciprocal influences of tumour products on the microvasculature. A more detailed understanding of the complex parameters that govern the interactions between the tumour and vascular compartments will help to improve anti-angiogenic strategies-- not only for cancer treatment, but also for preventing recurrence.

2,995 citations


Journal ArticleDOI
TL;DR: Attention has recently been focused on intracellular-signalling cascades as common molecular targets for various chemopreventive phytochemicals.
Abstract: Chemoprevention refers to the use of agents to inhibit, reverse or retard tumorigenesis. Numerous phytochemicals derived from edible plants have been reported to interfere with a specific stage of the carcinogenic process. Many mechanisms have been shown to account for the anticarcinogenic actions of dietary constituents, but attention has recently been focused on intracellular-signalling cascades as common molecular targets for various chemopreventive phytochemicals.

2,804 citations


Journal ArticleDOI
Yosef Shiloh1
TL;DR: Understanding ATM's mode of action provides new insights into the association between defective responses to DNA damage and cancer, and brings us closer to resolving the issue of cancer predisposition in some A-T carriers.
Abstract: Maintenance of genome stability is essential for avoiding the passage to neoplasia. The DNA-damage response--a cornerstone of genome stability--occurs by a swift transduction of the DNA-damage signal to many cellular pathways. A prime example is the cellular response to DNA double-strand breaks, which activate the ATM protein kinase that, in turn, modulates numerous signalling pathways. ATM mutations lead to the cancer-predisposing genetic disorder ataxia-telangiectasia (A-T). Understanding ATM's mode of action provides new insights into the association between defective responses to DNA damage and cancer, and brings us closer to resolving the issue of cancer predisposition in some A-T carriers.

2,579 citations


Journal ArticleDOI
TL;DR: Recent advances in understanding the biology and genetics of neuroblastomas have allowed classification into low-, intermediate- and high-risk groups, which allows the most appropriate intensity of therapy to be selected — from observation alone to aggressive, multimodality therapy.
Abstract: Neuroblastoma is a tumour derived from primitive cells of the sympathetic nervous system and is the most common solid tumour in childhood. Interestingly, most infants experience complete regression of their disease with minimal therapy, even with metastatic disease. However, older patients frequently have metastatic disease that grows relentlessly, despite even the most intensive multimodality therapy. Recent advances in understanding the biology and genetics of neuroblastomas have allowed classification into low-, intermediate- and high-risk groups. This allows the most appropriate intensity of therapy to be selected - from observation alone to aggressive, multimodality therapy. Future therapies will focus increasingly on the genes and biological pathways that contribute to malignant transformation or progression.

1,987 citations


Journal ArticleDOI
TL;DR: This work focuses on the JUN and FOS proteins and aims to offer a new perspective on the molecular mechanisms that regulate the oncogenic and anti-oncogenic effects of AP-1 in tumour development.
Abstract: The AP-1 transcription factor is a dimeric complex that contains members of the JUN, FOS, ATF and MAF protein families. AP-1 proteins are primarily considered to be oncogenic, but recent studies have challenged this view — some AP-1 proteins, such as JUNB and c-FOS, have been shown to have tumour-suppressor activity. Here, we focus on the JUN and FOS proteins and aim to offer a new perspective on the molecular mechanisms that regulate the oncogenic and anti-oncogenic effects of AP-1 in tumour development.

Journal ArticleDOI
TL;DR: The knowledge that has accumulated since their discovery 30 years ago has been remarkable, and should pave the way for not only solving the outstanding issues regarding RAS biology, but also for developing efficacious drugs that could have a significant impact on cancer treatment.
Abstract: From the pioneering work with acute transforming retroviruses to the current post-genomic era, RAS genes have always been at the leading edge of signal transduction and molecular oncology. Yet, a complete understanding of RAS function and dysfunction - mainly in human cancer - is still to come. The knowledge that has accumulated since their discovery 30 years ago has, however, been remarkable, and should pave the way for not only solving the outstanding issues regarding RAS biology, but also for developing efficacious drugs that could have a significant impact on cancer treatment.

Journal ArticleDOI
TL;DR: Understanding the association between chronic inflammation and cancer provides insights into the molecular mechanisms involved and highlights the interaction between nitric oxide and p53 as a crucial pathway in inflammatory-mediated carcinogenesis.
Abstract: Free radicals are ubiquitous in our body and are generated by normal physiological processes, including aerobic metabolism and inflammatory responses, to eliminate invading pathogenic microorganisms. Because free radicals can also inflict cellular damage, several defences have evolved both to protect our cells from radicals--such as antioxidant scavengers and enzymes--and to repair DNA damage. Understanding the association between chronic inflammation and cancer provides insights into the molecular mechanisms involved. In particular, we highlight the interaction between nitric oxide and p53 as a crucial pathway in inflammatory-mediated carcinogenesis.

Journal ArticleDOI
TL;DR: It seems that some tumours arise from small populations of 'cancer stem cells' that give rise to phenotypically diverse cancer cells, with less proliferative potential.
Abstract: Why are tumours heterogeneous, in terms of cell phenotype and proliferative potential, even in cases in which all cells are derived from a single clone? Ongoing mutagenesis can partially explain this heterogeneity, but it also seems that some tumours arise from small populations of 'cancer stem cells' that give rise to phenotypically diverse cancer cells, with less proliferative potential. These cancer stem cells are likely to arise from mutations that dysregulate normal stem-cell self-renewal. Using this information, it might be possible to devise more effective therapies.

Journal ArticleDOI
TL;DR: The basement membrane (BM) as mentioned in this paper is a specialized form of extracellular matrix (ECM) which mediates tissue compartmentalization and sends signals to epithelial cells about the external microenvironment.
Abstract: In recent years, the basement membrane (BM)--a specialized form of extracellular matrix (ECM)--has been recognized as an important regulator of cell behaviour, rather than just a structural feature of tissues. The BM mediates tissue compartmentalization and sends signals to epithelial cells about the external microenvironment. The BM is also an important structural and functional component of blood vessels, constituting an extracellular microenvironment sensor for endothelial cells and pericytes. Vascular BM components have recently been found to be involved in the regulation of tumour angiogenesis, making them attractive candidate targets for potential cancer therapies.

Journal ArticleDOI
TL;DR: The cytostatic and apoptotic functions of transforming growth factor-β (TGF-β) help restrain the growth of mammalian tissues; loss of these effects leads to hyperproliferative disorders and is common in cancer.
Abstract: The cytostatic and apoptotic functions of transforming growth factor-β (TGF-β) help restrain the growth of mammalian tissues; loss of these effects leads to hyperproliferative disorders and is common in cancer. However, tumour cells that are relieved from TGF-β growth constraints might then overproduce this cytokine to create a local immunosuppressive environment that fosters tumour growth and exacerbates the invasive and metastatic behaviour of the tumour cells themselves. For these reasons, there is a growing interest in understanding and therapeutically targeting TGF-β-mediated processes in cancer progression.

Journal ArticleDOI
TL;DR: The past few years have seen an explosion of interest in the epigenetics of cancer as a consequence of both the exciting coalescence of the chromatin and DNA methylation fields, and the realization thatDNA methylation changes are involved in human malignancies.
Abstract: The past few years have seen an explosion of interest in the epigenetics of cancer. This has been a consequence of both the exciting coalescence of the chromatin and DNA methylation fields, and the realization that DNA methylation changes are involved in human malignancies. The ubiquity of DNA methylation changes has opened the way to a host of innovative diagnostic and therapeutic strategies. Recent advances attest to the great promise of DNA methylation markers as powerful future tools in the clinic.

Journal ArticleDOI
TL;DR: What are the mechanisms by which this deadly combination of nicotine and carcinogens leads to 30% of cancer-related deaths in developed countries, and how can carcinogen biomarkers help to reveal these mechanisms?
Abstract: The devastating link between tobacco products and human cancers results from a powerful alliance of two factors - nicotine and carcinogens. Without either one of these, tobacco would be just another commodity, instead of being the single greatest cause of death due to preventable cancer. Nicotine is addictive and toxic, but it is not carcinogenic. This addiction, however, causes people to use tobacco products continually, and these products contain many carcinogens. What are the mechanisms by which this deadly combination leads to 30% of cancer-related deaths in developed countries, and how can carcinogen biomarkers help to reveal these mechanisms?

Journal ArticleDOI
TL;DR: In this paper, the identification and validation of translational targets for apoptosis-based cancer therapy has posed a great challenge, and the potential applicability in the clinic has been discussed.
Abstract: Acquisition of the ability to evade cellular suicide, or apoptosis, is one of the master switches that contributes to cellular transformation and, ultimately, to invasive cancer. Much has been learned about the molecular organization of apoptotic pathways and their regulators, but the identification and validation of translational targets for apoptosis-based cancer therapy has posed a great challenge. Survivin is an attractive candidate for cancer therapy, so what is its potential applicability in the clinic?

Journal ArticleDOI
TL;DR: A better understanding of the mechanisms that underlie this drug resistance should allow treatment to be optimized, so that substantial improvements in the outlook for women with this disease can be achieved.
Abstract: Ovarian cancer is responsible for 4% of deaths from cancer in women. Treatment comprises a combination of surgery and chemotherapy, but patients typically experience disease relapse within 2 years of the initial treatment. Further treatment can extend survival, although relapse eventually occurs again. A better understanding of the mechanisms that underlie this drug resistance should allow treatment to be optimized, so that substantial improvements in the outlook for women with this disease can be achieved.

Journal ArticleDOI
TL;DR: Research has recently been revitalized by the advent of novel molecular technologies that can identify cellular changes at the level of the genome or proteome, but how can these new technologies be harnessed to develop effective and practical screening tests?
Abstract: Early detection represents one of the most promising approaches to reducing the growing cancer burden. It already has a key role in the management of cervical and breast cancer, and is likely to become more important in the control of colorectal, prostate and lung cancer. Early-detection research has recently been revitalized by the advent of novel molecular technologies that can identify cellular changes at the level of the genome or proteome, but how can we harness these new technologies to develop effective and practical screening tests?

Journal ArticleDOI
TL;DR: Mechanisms by which LPA production or action could be modulated for cancer therapy are indicated.
Abstract: The bioactive phospholipid lysophosphatidic acid (LPA) stimulates cell proliferation, migration and survival by acting on its cognate G-protein-coupled receptors. Aberrant LPA production, receptor expression and signalling probably contribute to cancer initiation, progression and metastasis. The recent identification of ecto-enzymes that mediate the production and degradation of LPA, as well as the development of receptor-selective analogues, indicate mechanisms by which LPA production or action could be modulated for cancer therapy.

Journal ArticleDOI
TL;DR: Multiphoton microscopy has been developed for in vivo imaging and, using this technique, scientists are beginning to understand how invasive tumour cells move.
Abstract: Metastasis is the cause of death for patients with many types of cancer, but the process of tumour cell dissemination is poorly understood. As primary tumours are three-dimensional, departure of cells from primary tumours has been difficult to study. Multiphoton microscopy has been developed for in vivo imaging and, using this technique, we are beginning to understand how invasive tumour cells move.

Journal ArticleDOI
TL;DR: Although many studies have correlated deregulation of protein biosynthesis with cancer, it remains to be established whether this translates directly into an increase in cancer susceptibility, and under what circumstances.
Abstract: Ribosome biogenesis and translation control are essential cellular processes that are governed at numerous levels. Several tumour suppressors and proto-oncogenes have been found either to affect the formation of the mature ribosome or to regulate the activity of proteins known as translation factors. Disruption in one or more of the steps that control protein biosynthesis has been associated with alterations in the cell cycle and regulation of cell growth. Therefore, certain tumour suppressors and proto-oncogenes might regulate malignant progression by altering the protein synthesis machinery. Although many studies have correlated deregulation of protein biosynthesis with cancer, it remains to be established whether this translates directly into an increase in cancer susceptibility, and under what circumstances.

Journal ArticleDOI
TL;DR: Exploring the mechanism by which mutations in the FLT3 gene cause uncontrolled proliferation might lead to a better understanding of how cells become cancerous and provide insights for the development of new drugs.
Abstract: Normal haematopoietic cells use complex systems to control proliferation, differentiation and cell death. The control of proliferation is, in part, accomplished through the ligand-induced stimulation of receptor tyrosine kinases, which signal to downstream effectors through the RAS pathway. Recently, mutations in the FMS-like tyrosine kinase 3 (FLT3) gene, which encodes a receptor tyrosine kinase, have been found to be the most common genetic lesion in acute myeloid leukaemia (AML), occurring in approximately 25% of cases. Exploring the mechanism by which these FLT3 mutations cause uncontrolled proliferation might lead to a better understanding of how cells become cancerous and provide insights for the development of new drugs.

Journal ArticleDOI
TL;DR: The Hedgehog signalling pathway is essential for numerous processes during embryonic development, but the overall activity of the pathway is diminished after embryogenesis, recent reports show that the pathway remains active in some adult tissues, including adult stem cells in the brain and skin.
Abstract: The Hedgehog signalling pathway is essential for numerous processes during embryonic development. Members of this family of secreted proteins control cell proliferation, differentiation and tissue patterning in a dose-dependent manner. Although the overall activity of the pathway is diminished after embryogenesis, recent reports show that the pathway remains active in some adult tissues, including adult stem cells in the brain and skin. There is also evidence that uncontrolled activation of the pathway results in specific types of cancer.

Journal ArticleDOI
TL;DR: Proteomic analyses of early-stage cancers have provided new insights into the changes that occur in the early phases of tumorigenesis and represent a new resource of candidate biomarkers for early stage disease as discussed by the authors.
Abstract: The ability of physicians to effectively treat and cure cancer is directly dependent on their ability to detect cancers at their earliest stages. Proteomic analyses of early-stage cancers have provided new insights into the changes that occur in the early phases of tumorigenesis and represent a new resource of candidate biomarkers for early-stage disease. Studies that profile proteomic patterns in body fluids also present new opportunities for the development of novel, highly sensitive diagnostic tools for the early detection of cancer.

Journal ArticleDOI
TL;DR: The invasive nature of brain-tumour cells makes an important contribution to the ineffectiveness of current treatment modalities, as the remaining tumour cells inevitably infiltrate the surrounding normal brain tissue, which leads to tumour recurrence.
Abstract: The invasive nature of brain-tumour cells makes an important contribution to the ineffectiveness of current treatment modalities, as the remaining tumour cells inevitably infiltrate the surrounding normal brain tissue, which leads to tumour recurrence. Such local invasion remains an important cause of mortality and underscores the need to understand in more detail the mechanisms of tumour invasiveness. Several proteases influence the malignant characteristics of gliomas--could their inhibition prove to be a useful therapeutic strategy?

Journal ArticleDOI
TL;DR: There is mounting evidence that Notch signalling is not exclusively oncogenic and can instead function as a tumour suppressor.
Abstract: Notch signalling participates in the development of multicellular organisms by maintaining the self-renewal potential of some tissues and inducing the differentiation of others. Involvement of Notch in cancer was first highlighted in human T-cell leukaemia, fuelling the notion that aberrant Notch signalling promotes tumorigenesis. However, there is mounting evidence that Notch signalling is not exclusively oncogenic. It can instead function as a tumour suppressor.

Journal ArticleDOI
TL;DR: The gene expression profile of aggressive cutaneous and uveal melanoma cells resembles that of an undifferentiated, embryonic-like cell as mentioned in this paper, which has been termed "vasculogenic mimicry".
Abstract: The gene-expression profile of aggressive cutaneous and uveal melanoma cells resembles that of an undifferentiated, embryonic-like cell. The plasticity of certain types of cancer cell could explain their ability to mimic the activities of endothelial cells and to participate in processes such as neovascularization and the formation of a fluid-conducting, matrix-rich meshwork. This ability has been termed 'vasculogenic mimicry'. How does vasculogenic mimicry contribute to tumour progression, and can it be targeted by therapeutic agents?