{"title":"Cancer-associated stroma","authors":"W. Mesker, R. Tollenaar","doi":"10.1093/MED/9780198779452.003.0021_UPDATE_001","DOIUrl":"https://doi.org/10.1093/MED/9780198779452.003.0021_UPDATE_001","url":null,"abstract":"Tumorigenesis is a dynamic process. Research on cancer development and metastases focuses on the tumour ‘host’ interface, and in particular on the role of the stromal tissue. For a few decades now, it has been well established that the tumour-associated stroma affects cancer growth and progression. Fibroblasts of the stroma orchestrate the recruitment of immune cells to promote cancer growth. Moreover, the tumour stroma of each tumour is different in terms of quantity and of cellular composition. The tumour stroma has gained interest in the clinic with regard to patient prognosis and its potential to influence therapy response. Where cancer drug development traditionally focused on targeting the tumour cells, emphasis has now shifted towards the tumour microenvironment for the development of novel therapeutics.","PeriodicalId":417236,"journal":{"name":"Oxford Textbook of Cancer Biology","volume":"53 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122701645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Cancer metabolism","authors":"A. Schulze, K. Bensaad, A. Harris","doi":"10.1093/med/9780198779452.003.0016","DOIUrl":"https://doi.org/10.1093/med/9780198779452.003.0016","url":null,"abstract":"Abnormalities in cancer metabolism have been noted since Warburg first described the phenomenon of glycolysis in normoxic conditions. This chapter reviews the major pathways in metabolism known to be modified in cancer, including glycolysis and the Krebs cycle, the pentose shunt, and new data implicating the role of different metabolic adaptations, including oncometabolism. It highlights the genetic changes that effect metabolism including many of the commonly occurring oncogenes but also rare mutations that specifically target metabolism. Nutrient and oxygen limitation and proliferation create the microenvironmental selective stress for modifications in hypoxic metabolism, but also affect other cell types such as endothelial cells and macrophages. This range of changes provides many new therapeutic approaches. It also describes the potential value of targeting these adaptations and approaches to monitoring in vivo effects in patients to monitor therapeutic activity.","PeriodicalId":417236,"journal":{"name":"Oxford Textbook of Cancer Biology","volume":"29 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129878323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Hormones and cancer","authors":"B. Abderrahman, V. Jordan","doi":"10.1093/med/9780198779452.003.0010","DOIUrl":"https://doi.org/10.1093/med/9780198779452.003.0010","url":null,"abstract":"Breast and prostate cancer cells are regulated by sex steroids through their nuclear receptors. These receptor-positive cells are a major component of both cancers. The discovery of sex-steroid receptor regulation in breast, uterine, and prostate cancer has provided the most important targets in cancer therapeutics. This targeted therapeutic approach resulted in the enhanced survival of millions of patients worldwide. The biology of sex-steroid receptor regulation is discussed and individual therapeutic strategies are described. The molecular biology of acquired drug resistance in breast and prostate cancer is compared. Information linking mutations of sex-steroid receptors with acquired drug resistance is noted, as this is influencing future drug discovery with selective oestrogen receptor downregulators (SERDs). Current clinical approaches to subvert acquired drug resistance in breast and prostate cancer are also summarized.","PeriodicalId":417236,"journal":{"name":"Oxford Textbook of Cancer Biology","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131276844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Cancer stem cells","authors":"C. Sweeney, L. Quek, Betty Gration, P. Vyas","doi":"10.1093/MED/9780198779452.003.0020","DOIUrl":"https://doi.org/10.1093/MED/9780198779452.003.0020","url":null,"abstract":"The concept of cancer stem cells (CSCs) emerged from our understanding of the way in which normal tissues are generated from multipotent stem cells. Regenerative tissues exhibit a cellular hierarchy of differentiation, which is maintained by stem cells. Evidence from experimental models has indicated that a similar hierarchy is seen in at least some cancers, where CSCs give rise to disordered and dysfunctional tissues, leading to disease. The CSC model proposes that tumours can be divided into at least two distinct populations. The stem cells are a specialized population of cancer cells with the unique property of long-term self-renewal that maintain the growth of the cancerous clone. These stem cells give rise to the second population of cells, which form the bulk of the tumour, and lack indefinite self-renewal. Recently, our understanding of CSCs has been refined through combining genetic, epigenetic, and functional models of tumorigenesis. Malignant transformation occurs as the result of sequential acquisition of genetic mutations. Capacity for self-renewal is essential for a clone to survive and progress to become cancerous. If an oncogenic mutation occurs in a cell that is incapable of self-renewal, the clone will become exhausted through differentiation. CSCs may survive anticancer chemotherapy and increasing evidence indicates their role in mediating treatment resistance and relapse. Therefore, strategies to eradicate cancers must effectively target the stem cells that maintain their growth. CSC-directed therapeutic strategies are currently being explored in experimental studies and clinical trials but reducing toxicity to normal tissue stem cells represents a significant challenge.","PeriodicalId":417236,"journal":{"name":"Oxford Textbook of Cancer Biology","volume":"16 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126422534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Principles of chemotherapy","authors":"D. Kerr, D. Haller, J. Verweij","doi":"10.1093/MED/9780198779452.003.0028","DOIUrl":"https://doi.org/10.1093/MED/9780198779452.003.0028","url":null,"abstract":"Systemic cancer treatment stems initially from empirically discovered DNA synthesis inhibitors, which either deplete the cell of nucleotides, induce cross-link, or cause DNA single and double strand breaks or impair the cellular machinery of DNA repair, using mechanistically diverse drugs. A period of enlightenment followed, with anticancer drug development driven by an increased understanding of enzymes and pathways involved in cell signalling, control of angiogenesis, and epigenetics. This provided a parallel path towards precision cancer medicine where specific drugs can be targeted to patients with particular mutations. These include point mutations in RAS, which are used to exclude colorectal cancer patients from being treated with epidermal growth factor inhibitors; chromosomal translocations encoding fusion proteins which are cancer specific and serve as novel drug targets (e.g. BCR/ABL and imatinib, or EML4-ALK fusion oncogene and crizotinib). More recently, there has been a reanimation of immune approaches to cancer therapy with the clinical introduction of immune checkpoint inhibitors, designer T cells, and patient-specific antitumour vaccines. What next? It may be that next-generation sequencing provides an endless stream of so-called actionable mutations that permits tailored application of mutation-specific drugs, but so far there is little evidence of clinical benefit from such therapies.","PeriodicalId":417236,"journal":{"name":"Oxford Textbook of Cancer Biology","volume":"9 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124319872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Cancer biology through immunohistology","authors":"K. Pulford, K. Gatter","doi":"10.1093/MED/9780198779452.003.0027","DOIUrl":"https://doi.org/10.1093/MED/9780198779452.003.0027","url":null,"abstract":"Immunohistology is the microscopic study of cells and tissues using specific antibodies that bind to individual molecules expressed by the cellular and non-cellular components of the tissues. This branch of science is an essential link in the analysis and interpretation of data from high throughput genomic and proteomic technologies. Its use, both in the research and in the clinical arenas, has led to an increased understanding of cancer biology. This knowledge has also resulted in improvements in diagnosis, the provision of prognostic and predictive information, and highlighted the use of appropriate treatments. Furthermore, immunohistochemistry is a critical component in the search for personalized treatments. The ongoing advances in the availability of specific validated antibodies, continued improvements in staining and image analysis, and the integration of different technologies will ensure that immunohistochemistry becomes an even more essential tool in the study of cancer biology.","PeriodicalId":417236,"journal":{"name":"Oxford Textbook of Cancer Biology","volume":"7 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124835691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Cancer and cell death","authors":"J. Bullenkamp, M. Tavassoli","doi":"10.1093/MED/9780198779452.003.0014","DOIUrl":"https://doi.org/10.1093/MED/9780198779452.003.0014","url":null,"abstract":"Programmed cell death is an ordered and orchestrated cellular process that occurs in physiological and pathological conditions. Regulated programmed cell death is one of the mechanisms by which multicellular organisms limit the growth and replication of cells. Cell death is essential to control cell growth and tissue homeostasis; it occurs in normal tissues to allow the removal of damaged cells or to maintain a constant number of cells in regenerating tissues and plays an important part in embryogenesis. In an average human adult 50–70 billion cells undergo programmed cell death every day. The abundance of literature suggests that defects in programmed cell death play a crucial role in carcinogenesis. The genetic alterations in the cancer cell not only lead to increased cellular proliferation, as discussed in other chapters of this book, but also lead to loss of programmed cell death, thus increasing tumour growth. Despite being part of the problem, cell death plays an important role in the treatment of cancer as it is an important target of many treatment strategies. Unquestionably, apoptosis is the best-characterized and the most evolutionary conserved form of programmed cell death. Recently, many studies have demonstrated the existence of several other forms of programmed cell death including autophagy, necroptosis, and pyroptosis. In this chapter we discuss several regulated forms of cell death; we outline what we know about their mechanisms and how we can exploit this knowledge to reactivate programmed cell death in tumour cells for the treatment of cancer.","PeriodicalId":417236,"journal":{"name":"Oxford Textbook of Cancer Biology","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"130493973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Cancer immunology","authors":"H. Waldmann","doi":"10.1093/med/9780198779452.003.0023","DOIUrl":"https://doi.org/10.1093/med/9780198779452.003.0023","url":null,"abstract":"Until recently, the prospects for harnessing immune mechanisms to fight cancer were not encouraging. The advent of monoclonal antibodies, both as diagnostics and as probes for molecular function, have been important, while the identification of dendritic cells as a major intermediary between the antigen source and T-cell activation has been crucial. Major advances in molecular biology and the creation of mutant mice lacking defined gene products have pinpointed key molecules influencing immune function. Finally, many translational efforts in vaccination, autoimmune disease, and transplantation have enabled identification of hitherto undervalued mechanisms that the immune system uses to regulate itself. A fuller understanding of self-tolerance mechanisms, tumour antigens, and the tumour microenvironment has catalysed a wide range of novel therapeutic strategies and has also allowed a re-evaluation of mechanisms underlying the benefits of past chemotherapies.","PeriodicalId":417236,"journal":{"name":"Oxford Textbook of Cancer Biology","volume":"33 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128868131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Chemical carcinogens","authors":"D. Phillips","doi":"10.1093/med/9780198779452.003.0007","DOIUrl":"https://doi.org/10.1093/med/9780198779452.003.0007","url":null,"abstract":"Large geographical and temporal differences in cancer incidence indicate that the causes of the majority of cases are a consequence of environmental and lifestyle factors. While many of these remain unknown, around half have known causes, and these include chemicals in air, water, and food, as well as products of industrial processes and of combustion. The major classes of chemical carcinogens and how they were discovered are described. A property shared by many of them is that they, or one or more of their metabolites, are electrophiles that can damage DNA in mammalian cells, leading to cellular responses including DNA repair, cytotoxicity, apoptosis, mutagenesis, and malignant transformation. Methods for predicting the carcinogenicity of new chemicals are part of the regulatory processes for safety assessment, and sensitive methods for monitoring human exposure to carcinogens provide insight into the aetiology of cancer. The mutational signatures that genotoxic carcinogens leave in the tumours they induce provide evidence of the chemicals that have caused them, and the approach has promise for shedding light on the many as-yet-unidentified cases of cancer worldwide.","PeriodicalId":417236,"journal":{"name":"Oxford Textbook of Cancer Biology","volume":"323 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115565787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Cell cycle control","authors":"Simon M. Carr, N. L. La Thangue","doi":"10.1093/med/9780199656103.003.0004","DOIUrl":"https://doi.org/10.1093/med/9780199656103.003.0004","url":null,"abstract":"The cell cycle constitutes a series of events that lead to the duplication of the cell’s DNA and the generation of two new daughter cells. During the initial stages, the cell grows and expresses numerous genes in preparation for DNA replication, while during the final stages, this newly synthesized DNA is segregated to opposite poles of the cell and the cytoplasm is divided to generate two new daughters. To ensure proper progression from one cell cycle stage to another, the cell employs a number of control mechanisms (known as checkpoints), which constitute a complex set of signalling pathways that respond to both external and internal cues. When these checkpoints function incorrectly, as may occur in response to genetic mutation, the cell cycle control system begins to break down, and this can result in the onset of many human diseases including cancer. Our understanding of the molecular details of cell cycle control is therefore intimately linked with our ability to develop novel cancer therapy and has been a burgeoning area of scientific research for several decades. The molecular details of how the cellular checkpoints function will be summarized within this chapter, with specific examples given of genetic aberrations that compromise this control system, and how such mutations contribute to the onset of tumorigenesis.","PeriodicalId":417236,"journal":{"name":"Oxford Textbook of Cancer Biology","volume":"32 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122137832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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