Porth's Essentials of Pathophysiology, 4e

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Neoplasia

C h a p t e r 7

Host and Environmental Factors Because cancer is not a single disease, it is reasonable to assume that it does not have a single cause. More likely, cancers develop because of interactions among host and environmental factors. Among the host factors that have been linked to cancer are heredity, hormonal factors, obesity, and immunologic mechanisms. Environmental factors include chemical carcinogens, radiation, and microorganisms. Heredity The genetic predisposition for development of cancer has been documented for a number of cancerous and precancerous lesions that follow mendelian inheritance patterns. Two tumor suppressor genes, called BRCA1 (breast carcinoma 1) and BRCA2 (breast carcinoma 2), have been implicated in a genetic susceptibility to breast cancer. 2,3 These genes have also been associated with an increased risk of ovarian, prostate, pancreatic, colon, and other cancers. Several cancers exhibit an autosomal dominant inheritance pattern that greatly increases the risk of developing a tumor. The inherited mutation is usually a point mutation occurring in a single allele of a tumor-suppressor gene. Persons who inherit the mutant gene are born with one normal and one mutant copy of the gene. In order for cancer to develop, the normal allele must be inactivated, usually through a somatic mutation. As previously discussed, retinoblastoma is an example of a cancer that follows an autosomal dominant inheritance pattern. Approximately 40% of retinoblastomas are inherited, and carriers of the mutant RB suppressor gene have a 10,000-fold increased risk of developing retino- blastoma, usually with bilateral involvement. 2 Familial adenomatous polyposis of the colon also follows an autosomal dominant inheritance pattern. In people who inherit this gene, hundreds of adenomatous polyps may develop, some of which inevitably become malignant. Hormones Hormones have received considerable research atten- tion with respect to cancer of the breast, ovary, and endometrium in women and of the prostate and testis in men. Although the link between hormones and the development of cancer is unclear, it has been suggested that it may reside with the ability of hormones to drive the cell division of a malignant phenotype. 2 Because of the evidence that endogenous hormones affect the risk of these cancers, concern exists regarding the effects on cancer risk if the same or closely related hormones are administered for therapeutic purposes. Obesity There has been recent interest in obesity as a risk factor for certain types of cancer, including breast, endome- trial, and prostate cancer. 25 The process relating obesity to cancer development is multifactorial and involves a network of metabolic and immunologic mechanisms.

Obesity has been associated with insulin resistance and increased production of pancreatic insulin, both of which can have a carcinogenic effect. Insulin enhances insulin-like growth factor-1 (IGF-1) synthesis and its bioavailability. Both insulin and IGF-1 are anabolic molecules that can promote tumor development by stimulating cell proliferation and inhibiting apoptosis. Obesity has also been associated with increased levels of sex hormones (androgens and estrogens), which act to stimulate cell proliferation, inhibit apoptosis, and therefore increase the chance of malignant cell transfor- mation, particularly of endometrial and breast tissue, and possibly of other organs (e.g., prostate and colon cancer). And lastly, obesity has been related to a condi- tion of chronic inflammation characterized by abnormal production of inflammatory cytokines that can contrib- ute to the development of malignancies. Immunologic Mechanisms There is substantial evidence for the participation of the immune system in resistance against the progression and spread of cancer. 2,3,26 The central concept, known as the immune surveillance hypothesis, which was first proposed by Paul Ehrlich in 1909, postulates that the immune system plays a central role in protection against the development of tumors. 27 In addition to cancer–host interactions as a mechanism of cancer development, immunologic mechanisms provide a means for the detec- tion, classification, and prognostic evaluation of cancers and a potential method of treatment. Immunotherapy (discussed later in this chapter) is a cancer treatment modality designed to heighten the patient’s general immune responses so as to increase tumor destruction. The immune surveillance hypothesis suggests that the development of cancer might be associated with impairment or decline in the surveillance capacity of the immune system. For example, increases in cancer inci- dence have been observed in people with immunodefi- ciency diseases and in those with organ transplants who are receiving immunosuppressant drugs. The incidence of cancer also is increased in the elderly, in whom there is a known decrease in immune activity. The association of Kaposi sarcoma with acquired immunodeficiency syndrome (AIDS) further emphasizes the role of the immune system in preventing malignant cell prolifera- tion (discussed in Chapter 16). It has been shown that most tumor cells have molec- ular configurations that can be specifically recognized by immune cells or antibodies. These configurations are therefore called tumor antigens . Some tumor antigens are found only on tumor cells, whereas others are found on both tumor cells and normal cells; however, quantitative and qualitative differences in the tumor antigens permit the immune system to distinguish tumor from normal cells. 2 Virtually all of the components of the immune system have the potential for eradicating cancer cells, including T and B lymphocytes, natural killer (NK) cells, and mac- rophages (see Chapter 15). The T-cell response, which is responsible for direct killing of tumor cells and for activation of other components of the immune system, is