Chapter 18: Cancer
Chapter Summary
THE DEVELOPMENT AND CAUSES OF CANCER
Types of Cancer: Cancer can result from the abnormal proliferation of any type of cell. The most important distinction for the patient is between benign tumors, which remain confined to their site of origin, and malignant tumors, which can invade normal tissues and spread throughout the body.
The Development of Cancer: Tumors develop from single altered cells that begin to proliferate abnormally. Additional mutations lead to the selection of cells with progressively increasing capacities for proliferation, survival, invasion, and metastasis.
Causes of Cancer: Radiation and many chemical carcinogens act by damaging DNA and inducing mutations. Other chemical carcinogens contribute to the development of cancer by stimulating cell proliferation. Viruses also cause cancer in both humans and other species.
Properties of Cancer Cells: The uncontrolled proliferation of cancer cells is reflected in reduced requirements for extracellular growth factors and lack of inhibition by cell-cell contact. Many cancer cells are also defective in differentiation, consistent with their continued proliferation in vivo. The characteristic failure of cancer cells to undergo apoptosis also contributes substantially to tumor development.
Transformation of Cells in Culture: The development of in vitro assays for cell transformation has allowed the conversion of normal cells into tumor cells to be studied in cell culture.
TUMOR VIRUSES
Hepatitis B and C Viruses: The hepatitis B and C viruses cause liver cancer in humans.
SV40 and Polyomavirus: Although neither SV40 nor polyomavirus causes human cancer, they are important models for studying the molecular biology of cell transformation. SV40 T antigen induces transformation by interacting with the cellular Rb and p53 tumor suppressor proteins.
Papillomaviruses: Papillomaviruses induce tumors in a variety of animals, including cervical carcinoma in humans. Like SV40 T antigen, the transforming proteins of papillomaviruses interact with Rb and p53.
Adenoviruses: The adenoviruses do not cause naturally occurring cancers in either humans or other species but are important models in cancer research. Their transforming proteins also interact with Rb and p53.
Herpesviruses: The herpesviruses, which are among the most complex animal viruses, cause cancer in several species, including humans.
Retroviruses: Retroviruses cause cancer in humans and a variety of other animals. Some retroviruses contain specific genes responsible for inducing cell transformation, and studies of these highly oncogenic retroviruses have led to the characterization of both viral and cellular oncogenes.
ONCOGENES
Retroviral Oncogenes: The first oncogene to be identified was the src gene of RSV. Subsequent studies have identified more than two dozen distinct oncogenes in different retroviruses.
Proto-Oncogenes: Retroviral oncogenes originated from closely related genes of normal cells, called proto-oncogenes. The oncogenes are abnormally expressed or mutated forms of the corresponding proto-oncogenes.
Oncogenes in Human Cancer: A variety of oncogenes are activated by point mutations, DNA rearrangements, and gene amplification in human cancers. Some of these human tumor oncogenes, such as the ras genes, are cellular homologs of oncogenes that were first described in retroviruses.
Functions of Oncogene Products: Many oncogene proteins function as elements of signaling pathways that stimulate cell proliferation. The genes that encode cyclin D1 and Cdk4 can also act as oncogenes by stimulating cell cycle progression. Other oncogene proteins interfere with cell differentiation, and oncogenes encoding PI 3-kinase, Akt, and Bcl-2 inhibit apoptosis.
TUMOR SUPPRESSOR GENES
Identification of Tumor Suppressor Genes: In contrast to oncogenes, tumor suppressor genes inhibit tumor development. The prototype tumor suppressor gene, Rb, was identified by studies of inheritance of retinoblastoma. Loss or mutational inactivation of Rb and other tumor suppressor genes, including p53, contributes to the development of a wide variety of human cancers.
Functions of Tumor Suppressor Gene Products: The proteins encoded by most tumor suppressor genes act as inhibitors of cell proliferation or survival. The Rb, INK4, and p53 proteins are negative regulators of cell cycle progression. In addition, p53 is required for apoptosis induced by DNA damage and other stimuli, so its inactivation contributes to enhanced tumor cell survival. Some genes, such as BRCA1 and BRCA2, act to maintain genomic stability rather than directly influencing cell proliferation.
Roles of Oncogenes and Tumor Suppressor Genes in Tumor Development: Mutations in both oncogenes and tumor suppressor genes contribute to the progressive development of human cancers. Accumulated damage to multiple such genes results in the abnormalities of cell proliferation, differentiation, and survival that characterize the cancer cell.
MOLECULAR APPROACHES TO CANCER TREATMENT
Prevention and Early Detection: Many cancers can be cured if they are detected at early stages of tumor development. Genetic testing to identify individuals with inherited cancer susceptibilities may allow early detection and more effective treatment of high-risk patients.
Molecular Diagnosis: Detection of mutations in oncogenes and tumor suppressor genes may be useful in diagnosis and in monitoring response to treatment. Global analysis of gene expression may distinguish subclasses of cancers with differing clinical prognosis or response to treatment.
Treatment: The development of drugs targeted against specific oncogenes is beginning to lead to the discovery of new therapeutic agents that act selectively against cancer cells.
