Molecular Biology of Cancer

Fiona Macdonald, Christopher Ford, Alan Casson

• Publisher: Taylor & Francis
• Year: 2004
• eBook ISBN: 9781135321598
• Topic: Biological Sciences
• Subtopic: Biology
• Index: Biological Sciences

Molecular Biology of Cancer has been extensively revised and covers heredity cancer, microarray technology and increased study of childhood cancers. It continues to provide a detailed overview of the process which lead to the development and proliferation of cancer cells, including the techniques available for their study. It also describes the means by which tumor suppressor genes and oncogenes may be used in the diagnosis and in determining the prognosis of a wide variety of cancers, including breast, genitourinary, lung and gastrointestinal cancer.

1

General principles

1.1
Introduction

It has been realized for many years that cancer has a genetic component and at the level of the cell it can be said to be a genetic disease. In 1914, Boveri suggested that an aberration in the genome might be responsible for the origins of cancer. This was subsequently supported by the evidence that cancer, or the risk of cancer, could be inherited; that mutagens could cause tumors in both animals and humans; and that tumors are monoclonal in origin, that is, the cells of a tumor all show the genetic characteristics of the original transformed cell. It is only in recent years that the involvement of specific genes has been demonstrated at the molecular level.

Cancer cells contain many alterations which accumulate as tumors develop. Over the last 25 years, considerable information has been gathered on the regulation of cell growth and proliferation leading to the identification of the proto-oncogenes and the tumor suppressor genes. The proto-oncogenes encode proteins which are important in the control of cell proliferation, differentiation, cell cycle control and apoptosis. Mutations in these genes act dominantly and lead to a gain in function. In contrast the tumor suppressor genes inhibit cell proliferation by arresting progression through the cell cycle and block differentiation. They are recessive at the level of the cell although they show a dominant mode of inheritance. In addition, other genes are also important in the development of tumors. Mutations leading to increased genomic instability suggest defects in mismatch and excision repair pathways. Genes involved in DNA repair, when mutated, also predispose the patient to developing cancer. This failure of DNA repair is seen in xeroderma pigmentosum, ataxia telangiectasia, Fanconi’s anemia and Bloom’s syndrome [1]. In addition, many other genes encoding proteins, such as proteinases or other enzymes capable of disrupting tissues, and vascular permeability factors, have been shown to be involved in carcinogenesis. Epigenetic events such as alterations in the degree of methylation of DNA have also been detected in tumors [2]. Genomic imprinting, a process in which expression of two alleles is dependent on the parent of origin and controlled by changes in methylation, is now widely recognized in cancers [3]. Any combination of these changes may be found in an individual tumor. The overall progression to malignancy is therefore a complex event.

1.2
What is cancer?

In normal cell growth there is a finely controlled balance between growth-promoting and growth-restraining signals such that proliferation occurs only when required. The balance is tilted when increased cell numbers are required, for example during wound healing and during normal tissue turnover. Differentiation of cells during this process occurs in an ordered manner and proliferation ceases when no longer required. In tumor cells this process is disrupted, continued cell proliferation occurs and loss of differentiation may be found. In addition the normal process of programmed cell death may no longer operate.

Cancers arise from a single cell which has undergone mutation. Mutations in genes such as those described in the next three chapters give the cell increased growth advantages compared to others and allows them to escape normal controls on proliferation. The initial mutation will cause cells to divide to produce a genetically homogeneous clone. In turn, additional mutations occur which further enhance the cells’ growth potential. These mutations give rise to subclones within the tumor each with differing properties so that most tumors are heterogeneous. This multistep process is described further in Section 1.7.

Tumors can be divided into two main groups, benign or malignant. Benign tumors are rarely life threatening, grow within a well-defined capsule which limits their size and maintain the characteristics of the cell of origin and are thus usually well differentiated. Malignant tumors invade surrounding tissues and spread to different areas of the body to generate further growths or metastases. It is this process which is often the most life threatening. Different clones within a tumor will have differing abilities to metastasize, a property which is genetically determined. The process of metastasis is likely to involve several different steps and only a few clones within a tumor will have all of these properties. Some of the genes involved in the process of metastasis are described in subsequent chapters but additional factors such as proteinases, the cell adhesion molecules Ecadherin [4] and the integrin family have been implicated in the invasive process.

Tumor cells show a number of features which differentiate them from normal cells: (1) They are no longer as dependent on growth factors as normal cells either because they are capable of secreting their own growth factors to stimulate their own proliferation, a process termed autocrine stimulation, or because growth factor receptors on the surface are altered in such a way that binding of growth factors is no longer necessary to stimulate proliferation; (2) normal cells require contact with the surface in the extracellular environment to be able to grow whereas tumor cells are anchorage independent; (3) normal cells respond to the presence of other cells, and in culture will form a monolayer due to contact inhibition, whereas tumor cells lack this and often grow over or under each other; (4) tumor cells are less adhesive than normal cell...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Table of Contents
• Abbreviations
• Preface
• 1 General principles
• 2 Oncogenes
• 3 Tumor suppressor genes
• 4 Cell cycle control genes and mismatch repair genes
• 5 Hereditary cancers
• 6 Lung cancer
• 7 Colorectal cancer
• 8 Gastrointestinal cancer
• 9 Breast cancer
• 10 Genitourinary cancer
• 11 Leukemia and lymphoma
• 12 Childhood solid tumors
• 13 Therapeutic applications
• 14 Molecular techniques for analysis of genes
• Index