Showing papers in "Nature Reviews Cancer in 2002"
TL;DR: Epithelial–mesenchymal transition provides a new basis for understanding the progression of carcinoma towards dedifferentiated and more malignant states.
Abstract: Without epithelial–mesenchymal transitions, in which polarized epithelial cells are converted into motile cells, multicellular organisms would be incapable of getting past the blastula stage of embryonic development. However, this important developmental programme has a more sinister role in tumour progression. Epithelial–mesenchymal transition provides a new basis for understanding the progression of carcinoma towards dedifferentiated and more malignant states.
6,362 citations
TL;DR: It is shown that the MMPs have functions other than promotion of invasion, have substrates other than components of the extracellular matrix, and that they function before invasion in the development of cancer.
Abstract: Matrix metalloproteinases (MMPs) have long been associated with cancer-cell invasion and metastasis. This provided the rationale for clinical trials of MMP inhibitors, unfortunately with disappointing results. We now know, however, that the MMPs have functions other than promotion of invasion, have substrates other than components of the extracellular matrix, and that they function before invasion in the development of cancer. With this knowledge in hand, can we rethink the use of MMP inhibitors in the clinic?
5,860 citations
TL;DR: Small-molecule therapeutics that block PI3K signalling might deal a severe blow to cancer cells by blocking many aspects of the tumour-cell phenotype.
Abstract: One signal that is overactivated in a wide range of tumour types is the production of a phospholipid, phosphatidylinositol (3,4,5) trisphosphate, by phosphatidylinositol 3-kinase (PI3K) This lipid and the protein kinase that is activated by it — AKT — trigger a cascade of responses, from cell growth and proliferation to survival and motility, that drive tumour progression Small-molecule therapeutics that block PI3K signalling might deal a severe blow to cancer cells by blocking many aspects of the tumour-cell phenotype
5,654 citations
TL;DR: The ability to predict and circumvent drug resistance is likely to improve chemotherapy, and it has become apparent that resistance exists against every effective drug, even the authors' newest agents.
Abstract: Chemotherapeutics are the most effective treatment for metastatic tumours. However, the ability of cancer cells to become simultaneously resistant to different drugs--a trait known as multidrug resistance--remains a significant impediment to successful chemotherapy. Three decades of multidrug-resistance research have identified a myriad of ways in which cancer cells can elude chemotherapy, and it has become apparent that resistance exists against every effective drug, even our newest agents. Therefore, the ability to predict and circumvent drug resistance is likely to improve chemotherapy.
5,105 citations
TL;DR: Cells undergo a variety of biological responses when placed in hypoxic conditions, including activation of signalling pathways that regulate proliferation, angiogenesis and death, and many elements of the hypoxia-response pathway are good candidates for therapeutic targeting.
Abstract: Cells undergo a variety of biological responses when placed in hypoxic conditions, including activation of signalling pathways that regulate proliferation, angiogenesis and death. Cancer cells have adapted these pathways, allowing tumours to survive and even grow under hypoxic conditions, and tumour hypoxia is associated with poor prognosis and resistance to radiation therapy. Many elements of the hypoxia-response pathway are therefore good candidates for therapeutic targeting.
4,847 citations
TL;DR: Inhibition of the growth of metastases in secondary sites offers a promising approach for cancer therapy and could help to improve the treatment of metastatic disease.
Abstract: Metastases, rather than primary tumours, are responsible for most cancer deaths. To prevent these deaths, improved ways to treat metastatic disease are needed. Blood flow and other mechanical factors influence the delivery of cancer cells to specific organs, whereas molecular interactions between the cancer cells and the new organ influence the probability that the cells will grow there. Inhibition of the growth of metastases in secondary sites offers a promising approach for cancer therapy.
3,810 citations
TL;DR: A better understanding of how the Bcl2 family controls caspase activation should result in new, more effective therapeutic approaches in tissue homeostasis and cancer.
Abstract: Tissue homeostasis is regulated by apoptosis, the cell-suicide programme that is executed by proteases called caspases. The Bcl2 family of intracellular proteins is the central regulator of caspase activation, and its opposing factions of anti- and pro-apoptotic members arbitrate the life-or-death decision. Apoptosis is often impaired in cancer and can limit conventional therapy. A better understanding of how the Bcl2 family controls caspase activation should result in new, more effective therapeutic approaches.
3,768 citations
TL;DR: Links between human papillomaviruses (HPVs) and cervical cancer were first suspected almost 30 years ago and DNA of specific HPV types has since been found in almost all cervical cancer biopsies.
Abstract: Links between human papillomaviruses (HPVs) and cervical cancer were first suspected almost 30 years ago. DNA of specific HPV types has since been found in almost all cervical cancer biopsies. HPV oncogenes that are expressed in these cells are involved in their transformation and immortalization, and are required for the progression towards malignancy. Epidemiological studies have underlined that HPVs are the main aetiological factor for cervical cancer. But how has this knowledge been translated into the clinic to allow the prevention, screening and treatment of cervical cancer?
3,610 citations
TL;DR: Understanding the complex mechanisms that regulate whether or not a cell dies in response to p53 will ultimately contribute to the development of therapeutic strategies to repair the apoptotic p53 response in cancers.
Abstract: Compared with many normal tissues, cancer cells are highly sensitized to apoptotic signals, and survive only because they have acquired lesions — such as loss of p53 — that prevent or impede cell death. We are now beginning to understand the complex mechanisms that regulate whether or not a cell dies in response to p53 — insights that will ultimately contribute to the development of therapeutic strategies to repair the apoptotic p53 response in cancers.
3,242 citations
TL;DR: Recent evidence indicates that NF-κB and the signalling pathways that are involved in its activation are also important for tumour development.
Abstract: Nuclear factor of κB (NF-κB) is a sequence-specific transcription factor that is known to be involved in the inflammatory and innate immune responses. Although the importance of NF-κB in immunity is undisputed, recent evidence indicates that NF-κB and the signalling pathways that are involved in its activation are also important for tumour development. NF-κB should therefore receive as much attention from cancer researchers as it has already from immunologists.
2,436 citations
TL;DR: The most common human cancers — lung, breast and prostate — have a great avidity for bone, leading to painful and untreatable consequences.
Abstract: The most common human cancers --lung, breast and prostate -- have a great avidity for bone, leading to painful and untreatable consequences. What makes some cancers, but not others, metastasize to bone, and how do they alter its physiology? Some of the molecular mechanisms that are responsible have recently been identified, and provide new molecular targets for drug development.
TL;DR: What are the molecular mechanisms of tumour resistance to apoptosis and how can the authors use this knowledge to resensitize tumour cells to cancer therapy?
Abstract: Every cell in a multicellular organism has the potential to die by apoptosis, but tumour cells often have faulty apoptotic pathways. These defects not only increase tumour mass, but also render the tumour resistant to therapy. So, what are the molecular mechanisms of tumour resistance to apoptosis and how can we use this knowledge to resensitize tumour cells to cancer therapy?
TL;DR: As cancer cells undergo metastasis — invasion and migration of a new tissue — they penetrate and attach to the target tissue's basal matrix, which allows the cancer cell to pull itself forward into the tissue.
Abstract: As cancer cells undergo metastasis--invasion and migration of a new tissue--they penetrate and attach to the target tissue's basal matrix. This allows the cancer cell to pull itself forward into the tissue. The attachment is mediated by cell-surface receptors known as integrins, which bind to components of the extracellular matrix. Integrins are crucial for cell invasion and migration, not only for physically tethering cells to the matrix, but also for sending and receiving molecular signals that regulate these processes.
TL;DR: Understanding the host–microbial interactions that lead to neoplasia will improve cancer-targeted therapeutics and diagnostics, and provide mechanistic insights into other malignancies that arise within the context of microbially initiated inflammatory states.
Abstract: Although gastric adenocarcinoma is associated with the presence of Helicobacter pylori in the stomach, only a small fraction of colonized individuals develop this common malignancy. H. pylori strain and host genotypes probably influence the risk of carcinogenesis by differentially affecting host inflammatory responses and epithelial-cell physiology. Understanding the host-microbial interactions that lead to neoplasia will improve cancer-targeted therapeutics and diagnostics, and provide mechanistic insights into other malignancies that arise within the context of microbially initiated inflammatory states.
TL;DR: Cytotoxic chemotherapy or radiotherapy of cancer is limited by serious, sometimes life-threatening, side effects that arise from toxicities to sensitive normal cells because the therapies are not selective for malignant cells, so how can selectivity be improved?
Abstract: Cytotoxic chemotherapy or radiotherapy of cancer is limited by serious, sometimes life-threatening, side effects that arise from toxicities to sensitive normal cells because the therapies are not selective for malignant cells. So how can selectivity be improved? One strategy is to couple the therapeutics to antibodies or other ligands that recognize tumour-associated antigens. This increases the exposure of the malignant cells, and reduces the exposure of normal cells, to the ligand-targeted therapeutics.
TL;DR: Positron emission tomography is a highly sensitive non-invasive technology that is ideally suited for pre-clinical and clinical imaging of cancer biology, in contrast to anatomical approaches.
Abstract: The imaging of specific molecular targets that are associated with cancer should allow earlier diagnosis and better management of oncology patients. Positron emission tomography (PET) is a highly sensitive non-invasive technology that is ideally suited for pre-clinical and clinical imaging of cancer biology, in contrast to anatomical approaches. By using radiolabelled tracers, which are injected in non-pharmacological doses, three-dimensional images can be reconstructed by a computer to show the concentration and location(s) of the tracer of interest. PET should become increasingly important in cancer imaging in the next decade.
TL;DR: Angiogenesis inhibitors are a new class of drugs, for which the general rules involving conventional chemotherapy might not apply, and clinical application depends partly on the transfer of expertise from scientists who are familiar with the biology of angiogenesis to clinicians.
Abstract: Angiogenesis inhibitors are a new class of drugs, for which the general rules involving conventional chemotherapy might not apply. The successful translation of angiogenesis inhibitors to clinical application depends partly on the transfer of expertise from scientists who are familiar with the biology of angiogenesis to clinicians. What are the most common questions that clinicians ask as they begin to test angiogenesis inhibitors in cancer clinical trials?
TL;DR: The RAS oncogenes are members of a large family of small GTPases that bind GTP and hydrolyse it to GDP and the switching between these two states regulates a wide range of cellular processes.
Abstract: The RAS oncogenes were identified almost 20 years ago. Since then, we have learnt that they are members of a large family of small GTPases that bind GTP and hydrolyse it to GDP. This is then exchanged for GTP and the cycle is repeated. The switching between these two states regulates a wide range of cellular processes. A branch of the RAS family--the RHO proteins--is also involved in cancer, but what is the role of these proteins and would they make good therapeutic targets?
TL;DR: The ability of tumours to induce new blood-vessel formation has been a major focus of cancer research over the past few decades, and vascular endothelial growth factor (VEGF) is now known to be central to this process.
Abstract: The ability of tumours to induce new blood-vessel formation has been a major focus of cancer research over the past few decades, and vascular endothelial growth factor (VEGF) is now known to be central to this process. The quest for VEGF and other factors that promote tumour angiogenesis was initiated many decades ago, and a long and complicated path has led to the development of inhibitors of these molecules as anticancer agents. How did this field begin, and how have we arrived at our present understanding of the role of VEGF in tumour progression.
TL;DR: Cancer cells often develop resistance to chemotherapy or irradiation through mutations in the p53 tumour-suppressor gene, which prevent apoptosis induction in response to cellular damage, so agents that are designed to activate death receptors or block decoy receptors might be used to kill tumour cells that are resistant to conventional cancer therapies.
Abstract: Cancer cells often develop resistance to chemotherapy or irradiation through mutations in the p53 tumour-suppressor gene, which prevent apoptosis induction in response to cellular damage. Death receptors — members of the tumour-necrosis factor receptor (TNFR) superfamily — signal apoptosis independently of p53. Decoy receptors, by contrast, are a non-signalling subset of the TNFR superfamily that attenuate death-receptor function. Agents that are designed to activate death receptors (or block decoy receptors) might therefore be used to kill tumour cells that are resistant to conventional cancer therapies.
TL;DR: It is now recognized that MMP activity is tightly regulated at several levels, providing new avenues for blocking these enzymes and leading to new therapeutic strategies for cancer.
Abstract: For more than two decades, the view that tumour-associated matrix metalloproteinases (MMPs) were required for peritumour tissue degradation and metastasis dominated the drive to develop MMP inhibitors as anticancer therapeutics. Until recently, clinical trials with MMP inhibitors have yielded disappointing results, highlighting the need for better insight into the mechanisms by which this growing family of multifunctional enzymes contribute to tumour growth. It is now recognized that MMP activity is tightly regulated at several levels, providing new avenues for blocking these enzymes. What are the different approaches that can be used to target MMPs, and which of these might lead to new therapeutic strategies for cancer?
TL;DR: A new generation of agents that target DNA-associated processes are anticipated to be far more specific and effective in cancer therapeutics.
Abstract: DNA is the molecular target for many of the drugs that are used in cancer therapeutics, and is viewed as a non-specific target of cytotoxic agents. Although this is true for traditional chemotherapeutics, other agents that were discovered more recently have shown enhanced efficacy. Furthermore, a new generation of agents that target DNA-associated processes are anticipated to be far more specific and effective. How have these agents evolved, and what are their molecular targets?
TL;DR: Regulatable transgenic mouse models of oncogenesis have shed light on the role of c-MYC in tumour progression and provide hope for effective cancer therapies.
Abstract: Deregulated expression of c-MYC occurs in a broad range of human cancers and is often associated with poor prognosis, indicating a key role for this oncogene in tumour progression. However, as established human tumours often bear multiple genetic lesions, it is difficult to determine whether c-MYC is instrumental in the initiation/progression of the tumour, or indeed whether inactivating c-MYC would lead to tumour regression. Regulatable transgenic mouse models of oncogenesis have shed light on these issues and provide hope for effective cancer therapies.
TL;DR: This poster focuses on pancreatic ductal adenocarcinoma, a disease characterized by invasiveness, rapid progression and profound resistance to treatment.
Abstract: Pancreatic ductal adenocarcinoma is an aggressive and devastating disease, which is characterized by invasiveness, rapid progression and profound resistance to treatment. Advances in pathological classification and cancer genetics have improved our descriptive understanding of this disease; however, important aspects of pancreatic cancer biology remain poorly understood. What is the pathogenic role of specific gene mutations? What is the cell of origin? And how does the stroma contribute to tumorigenesis? A better understanding of pancreatic cancer biology should lead the way to more effective treatments.
TL;DR: A limited list of transcription factors are overactive in most human cancer cells, which makes them targets for the development of anticancer drugs and how could specific transcription-factor activity be inhibited?
Abstract: A limited list of transcription factors are overactive in most human cancer cells, which makes them targets for the development of anticancer drugs. That they are the most direct and hopeful targets for treating cancer is proposed, and this is supported by the fact that there are many more human oncogenes in signalling pathways than there are oncogenic transcription factors. But how could specific transcription-factor activity be inhibited?
TL;DR: By rationalizing the shared and unique elements of human and mouse models of cancer, this work should be able to identify the molecular circuits that function differently in humans and mice, and use this knowledge to improve existing models ofcancer.
Abstract: Cancer arises from a stepwise accumulation of genetic changes that liberates neoplastic cells from the homeostatic mechanisms that govern normal cell proliferation. In humans, at least four to six mutations are required to reach this state, but fewer seem to be required in mice. By rationalizing the shared and unique elements of human and mouse models of cancer, we should be able to identify the molecular circuits that function differently in humans and mice, and use this knowledge to improve existing models of cancer.
TL;DR: Clinical studies in cancer patients have shown that nutritional supplementation can be effective when combined with agents that attenuate the action of tumour factors and modifiers of the central effects on appetite might also show promise.
Abstract: Cachexia — the massive (up to 80%) loss of both adipose tissue and skeletal muscle mass — is a significant factor in the poor performance status and high mortality rate of cancer patients. Although this metabolic defect has been known since cancer was first studied, it is only recently that major advances have been made in the identification of catabolic factors that act to destroy host tissues during the cachectic process. Although anorexia is frequently present, depression of food intake alone seems not to be responsible for the wasting of body tissues, as nutritional supplementation or pharmacological manipulation of appetite is unable to reverse the catabolic process — particularly with respect to skeletal muscle. However, recent clinical studies in cancer patients have shown that nutritional supplementation can be effective when combined with agents that attenuate the action of tumour factors and modifiers of the central effects on appetite might also show promise.
TL;DR: The mechanisms that underlie many breast tumours either fail to respond or become resistant to endocrine therapies are understood to develop strategies for overcoming or bypassing it.
Abstract: Deaths from breast cancer have fallen markedly over the past decade due, in part, to the use of endocrine agents that reduce the levels of circulating oestrogens or compete with oestrogen for binding to its receptor. However, many breast tumours either fail to respond or become resistant to endocrine therapies. By understanding the mechanisms that underlie this resistance, we might be able to develop strategies for overcoming or bypassing it.
TL;DR: Multiple myeloma is a neoplasm of terminally differentiated B cells (plasma cells) in which chromosome translocations frequently place oncogenes under the control of immunoglobulin enhancers.
Abstract: Multiple myeloma is a neoplasm of terminally differentiated B cells (plasma cells) in which chromosome translocations frequently place oncogenes under the control of immunoglobulin enhancers. Unlike most haematopoietic cancers, multiple myeloma often has complex chromosomal abnormalities that are reminiscent of epithelial tumours. What causes full-blown myeloma? And can our molecular understanding of this common haematological malignancy be used to develop effective preventive and treatment strategies?
TL;DR: Recent studies of the von Hippel–Lindau gene have helped to decipher how cells sense changes in oxygen availability, and have revealed a previously unappreciated role of prolyl hydroxylation in intracellular signalling.
Abstract: The von Hippel-Lindau hereditary cancer syndrome was first described about 100 years ago. The unusual clinical features of this disorder predicted a role for the von Hippel-Lindau gene (VHL) in the oxygen-sensing pathway. Indeed, recent studies of this gene have helped to decipher how cells sense changes in oxygen availability, and have revealed a previously unappreciated role of prolyl hydroxylation in intracellular signalling. These studies, in turn, are laying the foundation for the treatment of a diverse set of disorders, including cancer, myocardial infarction and stroke.