This chapter focuses on the process of forming new blood vessels from pre-existing ones by the growth and migration of endothelial cells — angiogenesis. It argues that this process is common during embryogenesis, although it rarely occurs in the adult. The chapter then shows why angiogenesis is essential for most tumors with respect to cancer. It explains the angiogenic switch and the mechanisms of angiogenic sprouting. Sprouting of pre-existing vessels requires major reorganization involving destabilization of the mature vessel, proliferation and migration of endothelial cells, and maturation. It is regulated by the interaction of soluble mediators and their cognate receptors. The chapter then presents the other means of tumor neovascularization and elaborates on anti-angiogenic therapy. It then looks at vascular targeting by vascular disrupting agents.
This chapter begins with a description of apoptosis. It defines apoptosis as a type of “cell suicide” that is intrinsic to the cell. It is an active process requiring the expression of genetically encoded proteins that every cell is capable of executing. The chapter then chronicles the molecular mechanisms of apoptosis and examines specific mutations that affect the apoptotic pathway and play a role in carcinogenesis. It also investigates how mutations in the apoptotic pathway can lead to resistance to chemotherapeutic drugs. Next, the chapter presents strategies for the design of new cancer therapeutics that target apoptosis. It also studies how caspases play a central role in apoptosis.
Aysha Divan and Janice A. Royds
Cancer Biology and Treatment starts off by describing the fundamentals of canceras a disease of the genome. It then looks at the pathology of cancer. It also examines molecular epidemiology and looks at key players and pathways in cancer. Cancer treatment and cancer management are important topics to consider in this field. Finally, the text looks at major challenges and new opportunities in the study and research of cancer.
This chapter provides an overview of the fundamentals of cancer. Normal cells evolve to become cancer cells by acquiring successive mutations in primarily two classes of genes: the proto-oncogenes and the tumour suppressor genes. Mutations that specifically drive cancer development and disease progression are called driver mutations; the rest are termed passenger mutations and their role in carcinogenesis is less clear. Large-scale cancer genome studies have provided deep insight into the mutational profile of the cancer genome, and are presently informing not only basic research but also the clinical management of cancer patients. The chapter then looks at cancer stem cells, which have the capacity to self-renew and differentiate into cell types that recreate the cellular heterogeneity of the tumour from which they derive. Viruses are also associated with the development of some cancers as are certain bacteria.
The cancer genome: mutations versus repair
This chapter looks at the structures of genes and describes the mutations that occur during carcinogenesis. It argues that changes in the nucleotide sequence of DNA — called mutations — are crucial for acquiring the hallmarks of cancer and have been labeled an enabling characteristic. The chapter then investigates how, on the one hand, mutations in DNA occur as a consequence of exposure to carcinogens and, on the other hand, examine the DNA repair systems that are in place to maintain the integrity of the genome and suppress tumorigenesis. The chapter then shifts to define the genetic information, coded within DNA, and the role of the accumulation of mutations. Ultimately, the chapter concludes with a discussion of conventional chemotherapies and a new class of drugs that target DNA repair pathways. It also studies the recent findings from advances in sequencing technology and imaging.
Cancer stem cells and the regulation of self-renewal and differentiation pathways: focus on colon cancer and leukemias
This chapter begins with an overview of the process of differentiation during development and in the adult. It outlines the characteristics of cells at different degrees of differentiation and discusses their relationship to cancer. The chapter also covers the review of the “cancer stem cell model” that states that subpopulations of cells with stem cell properties initiate and maintain the cancer phenotype. These cells often reside in distinct microenvironments in tumors, called stem cell niches. Signals from the stem cell niche dictate stem cell fate and behaviour. The chapter then reviews the molecular mechanisms that underlie the regulation of self-renewal and examines specific mutations in these pathways that can lead to cancer. Finally, the chapter elaborates on the new cancer therapeutics designed to target aspects of self-renewal and differentiation pathways.
Cancer Treatment and Clinical Management
This chapter presents an overview of cancer prognosis and current treatments such as surgery, radiotherapy, and chemotherapy. It begins by looking at cancer prevention. Predicting the expected outcome for patients diagnosed with cancer is a critical step in their management; however, prognostication has remained somewhat subjective, leading to suboptimal clinical outcomes. The chapter then considers immunotherapy, which aims to treat cancer by generating or enhancing an immune response against the tumour. Immunotherapy differs from other methods of cancer treatment in that it does not target the tumour cell directly but instead targets the immune system. Principally, three strategies are utilized: immune checkpoint blockade, adoptive T cell transfer, and cancer vaccines. The chapter also describes how clinical trials of new candidate drugs are currently undertaken.
The cell cycle
Jorrit M. Enserink, Helene Knævelsrud, and Joseph M. Robertson
This chapter highlights the basic mechanism and regulation of the cell cycle. It defines the cell cycle as the ordered series of events that lead to duplication of the chromosomes and other cellular components, followed by cell division. The chapter emphasizes that the cell cycle is made up of four stages: G1, S phase, G2, and M phase. G1, S phase, and G2 constitute the cycle phase called interphase. The genetic material of a cell is replicated in S phase (DNA synthesis), and M phase involves partitioning of the cell and genome. The chapter then introduces the cyclins and cyclin-dependent kinases (CDKs), the main players in the cell cycle. It also investigates the molecular mechanisms involved in the regulation of the cell cycle. Next, it describes specific mutations that affect the cell cycle and play a role in carcinogenesis. It also discusses therapeutic strategies that target molecules of the cell cycle.
Growth factor signaling and oncogenes
This chapter focuses on one of the fundamental characteristics of cells: their ability to self-reproduce. It stresses that the process of cell division (also known as cell proliferation or cell growth) must be carefully regulated, and DNA replication must be precisely coordinated in order to maintain the integrity of the genome for each cell generation. The chapter then moves to explicate the process of transferring a signal across a cell called signal transduction. It demonstrates the four types of proteins involved in the transduction of a growth factor signal: growth factors, growth factor receptors, intracellular signal transducers, and nuclear transcription factors, which elicit the mitogenic effect through the regulation of gene expression. Towards the end, the chapter identifies a common thread in many growth factor signal transduction pathways: many growth factor receptors are tyrosine kinases. It then reviews some examples of signal transducers.
Inflammation, infection, and the microbiome
This chapter examines the molecular mechanisms of chronic inflammation that enable carcinogenesis. It highlights that chronic inflammation is an enabling characteristic of cancer. Inflammation is part of the immune response against infectious agents and injury, and is a consequence of wound healing. The chapter reveals that lingering chronic inflammation plays an important role in both cancer initiation and promotion. The chapter also identifies infectious agents that are considered to be carcinogens, and describes several modes of action of these infectious agents, including the induction of inflammation. Finally, the chapter presents an examination of how alterations of the microbiome may play a role in cancer. The microbiome is an ecological community of commensal, symbiotic, and pathogenic microorganisms that share our body space. The chapter concludes with a report on the major therapeutic applications of this knowledge.
This chapter aims to provide a foundation in the molecular biology of cancer and to demonstrate the conceptual process that is being pursued in order to design more specific cancer drugs. It discusses the translation of the knowledge of molecular pathways into clinically important therapies, then introduces a foundation in the cell and molecular biology of cancer. The chapter also reviews the terminology of cancer and the mechanisms of cellular processes. The chapter then shifts to look at the intricacies of cell function and the molecular pathways that underlie the process of carcinogenesis, whereby a normal cell is transformed into a cancer cell. It ultimately considers cancer cells in the context of the entire body.
Key Players and Pathways in Cancer
This chapter introduces signalling pathways and their relationship to cancer. The signalling pathways that are perturbed during tumour initiation and progression underpin the hallmarks of cancer. In general, tumour cells exhibit elevated cell proliferation, repressed cell death, and decreased differentiation relative to normal cells. Altered signalling in tumours was at first considered to involve linear pathways, but it is now recognized that a network view, with essential cross-talk between signalling hubs, is entailed. Thus, cancer-associated genes form key nodes or hubs in a complex of signalling pathways. Some oncogene/tumour suppressor 'products', none more so than p53, satisfy the criteria of being important nodes and are critical for our understanding of carcinogenesis. The chapter then considers telomeres, non-coding RNAs, changes in the cell's metabolism, and tumour immunity.
Major Challenges and New Opportunities in Cancer
This chapter highlights the major challenges and new opportunities in the study and research of cancer. Despite the advances in the development of more targeted therapies and of new treatment modalities, a number of areas continue to challenge the successful treatment of cancer. These include metastatic tumour spread and resistance to therapy. Nevertheless, the cancer genomics revolution, combined with the development of new technologies such as single-cell analysis, has also created substantial opportunities, leading to the identification and use of biomarkers in the clinical management of cancer and enabling the monitoring of disease resistance. These in turn are facilitating the use of more personalized treatment regimes based on the molecular profile of the patient's tumour, including precision cancer medicine and cancer gene therapy. The chapter also looks at new directions in cancer immunotherapy.
This chapter concentrates on the process by which tumor cells from a primary site invade and migrate to other parts of the body — metastasis. It stresses that metastasis, a hallmark of cancer, is the fundamental difference between a benign and a malignant growth, and represents the major clinical problem of cancer. The chapter then analyzes how tumors spread, then looks at the process of metastasis. It also discusses the nature of invasion and the epithelial-mesenchymal transition as well as the intravasation, transport, and extravasation. The spread of cells throughout the body results in physical obstruction, competition with normal cells for nutrients and oxygen, and invasion and interference with organ function. The chapter then shifts to review metastatic colonization and organotropism. It ultimately concludes by explicating metalloproteinase inhibitors and the strategies for restoring metastasis suppressors.
Molecular Biology of Cancer starts with an introduction. It then looks at the cancer genome. Other chapters consider the regulation of gene expression, growth factor signaling, and oncogenes. The cell cycle is also considered, as are tumor suppressor genes. The text moves on to look at apoptosis, cancer stem cells and the regulation of self-renewal and differentiation pathways. There are also chapters on metastasis, angiogenesis, reprogrammed metabolism and diet, tumor immunology and immunotherapy, and inflammation and infection. Finally, the text considers strategies and tools for research and for drug development.
This chapter examines the influence of genetics, environmental factors, and lifestyle behaviours on the risk of cancer developing. It begins by describing global cancer trends, including incidence, mortality, geographical variations, and gender variations. Cancers can be familial (inherited) or sporadic. In inherited cancers, the disease causing mutation is carried in the germline and so is present in all cells of the body at birth. This does not cause cancer on its own and additional somatic mutations are still required for cancer to develop. However, only about 5–10 per cent of all cancers result directly from gene defects inherited from a parent. The rest occur through mutations acquired in somatic cells, and are sporadic. These mutations can arise due to exposure to certain environmental factors, lifestyle behaviours, and some infectious agents as well as spontaneous mutations arising, for example through errors in DNA replication.
Pathology of Cancer
This chapter discusses the pathology of cancer. Tumours are behaviourally classified as benign or malignant based on characteristics identified by the physician, pathologist, or radiologist. In addition to benign or malignant, a further important classification that determines treatment and prognosis is the morphological classification. This is based on the type of malignant cell and its degree of differentiation. There are various stages in diagnosis of solid tumours, starting with gross examination and then imaging, and finally histology. Meanwhile, cancer screening involves looking for cancer before a person has any symptoms, with the aim of catching cancer at an early stage when it is easier to treat. Douglas Hanahan and Robert Weinberg first coined the term 'hallmarks of cancer' in 2000 to describe the essential biological processes necessary for tumour formation. These hallmarks are generalized features that are considered fundamental to cancer cell biology.
Regulation of gene expression
This chapter analyzes the molecular components involved in gene expression, including transcription factors, chromatin modifications and chromatin-binding proteins, non-coding RNAs (ncRNAs), and telomeres, and how they can contribute to the processes underpinning cancer. It emphasizes that gene expression may be modulated in various ways: through the regulation of transcription, chromatin structure, and post-transcriptional mechanisms. The chapter also describes the structure of a gene within the context of chromatin in order to elucidate how gene and chromatin structure affects gene expression. Next, the chapter displays the roles of ncRNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) that play a role in gene regulation, including post-transcriptional gene expression. It also assesses the effect of telomere position and length on gene expression.
Reprogrammed metabolism and diet
This chapter highlights the role of diet in cancer prevention and causation. It explores our understanding that some food constituents exert their cancer-relevant effects by their ability to regulate gene expression: a paradigm of how environmental factors work together with genes, rather than the concept of environment versus genes. The chapter also describes the new therapeutic approaches that exploit our knowledge of reprogrammed metabolism and the molecular mechanisms of food constituents. The chapter then shifts to demonstrate the preventative factors of diet and causative factors of diet. It also investigates the link between nutrients, cancer, and hormone action. Next, the chapter addresses the drug strategies that target metabolic pathways. It also considers “enhanced” foods and dietary supplements for chemoprevention.
Strategies and tools for research and clinical development
This chapter recalls the goal of cancer research: to reveal fundamental mechanisms of cancer biology in order to produce preventative and therapeutic agents. The chapter addresses both strategies and tools of research and drug development. It starts with a description of the scientific method used to uncover the fundamentals of the role of extrachromosomal DNA (ecDNA) in cancer. This chapter shows how simple observation can lead to the understanding of how the genomes of cancer cells can change and how this knowledge is revealing clinical implications and candidate targets for a new class of therapeutics. The chapter also describes several select experimental methods and tools that have wide applications. Finally, the chapter pays attention to the use of the CRISPR-Cas9 system — one of the newest additions to the tools for investigating cancer genes. It also considers candidate drugs and some aspects of clinical trial design.