Porth's Essentials of Pathophysiology, 4e

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Cell and Tissue Function

U N I T 1

The accumulation of cancer cells may result not only from the activation of growth-promoting oncogenes or inactivation of tumor-suppressor genes, but also from genes that regulate cell death through apoptosis or pro- grammed cell death. 2,3,21,22 Faulty apoptotic mechanisms have an important role in cancer. The failure of can- cer cells to undergo apoptosis in a normal manner may be due to a number of problems. There may be altered cell survival signaling, down-regulation of death recep- tors, stabilization of the mitochondria, or inactivation of proapoptotic proteins. Alterations in apoptotic and antiapoptotic pathways have been found in many can- cers. One example is the high levels of the antiapoptotic protein BCL2 that occur secondary to a chromosomal translocation in certain B-cell lymphomas. The mito- chondrial membrane is a key regulator of the balance between cell death and survival. Proteins in the BCL2 family reside in the inner mitochondrial membrane and are either proapoptotic or antiapoptotic. Since apoptosis is considered a normal cellular response to DNA dam- age, loss of normal apoptotic pathways may contribute to cancer by enabling DNA-damaged cells to survive. Even with all the genetic abnormalities described ear- lier, tumors cannot enlarge unless angiogenesis occurs and supplies them with the blood vessels necessary for survival. Angiogenesis is required not only for continued tumor growth, but also for metastasis. 2,3,23 The molecu- lar basis for the angiogenic switch is unknown, but it appears to involve increased production of angiogenic factors or loss of angiogenic inhibitors. These factors may be produced directly by the tumor cells themselves or by inflammatory cells (e.g., macrophages) or other stromal cells associated with the tumors. In normal cells, the p53 gene can stimulate expression of antiangiogenic molecules and repress expression of proangiogenic molecules, such as vascular endothelial growth factor (VEGF). 2 Thus, loss of p53 activity in cancer cells both promotes angiogenesis and removes an antiangiogenic switch. Because of the crucial role of angiogenic factors in tumor growth, much interest is focused on the devel- opment of antiangiogenesis therapy. Finally, multiple genes and molecular and cellular pathways are known to be involved in tumor invasion and metastasis. Evidence suggests that genetic pro- grams that are normally operative in stem cells dur- ing embryonic development may become operative in cancer stem cells, enabling them to detach, cross tis- sue boundaries, escape death by anoikis or apoptosis, and colonize new tissues. 24 The MET proto-oncogene, which is expressed in both stem and cancer cells, is a key regulator of invasive growth. Recent findings sug- gest that adverse conditions such as tissue hypoxia, which are commonly present in cancerous tumors, trigger this invasive behavior by activating the MET tyrosine kinase receptor. Tumor Cell Transformation The process by which carcinogenic agents cause nor- mal cells to become cancer cells is hypothesized to be a multistep mechanism that can be divided into three

Normal cell

Normal cell line

Carcinogenic agent (chemicals, radiation, viruses)

DNA damage and cell mutation

Initiation

Mutated cell

Activation of oncogenes by promoter agent

Promotion

Progression

Malignant tumor

stages: initiation, promotion, and progression (Fig. 7-9). Initiation involves the exposure of cells to doses of a carcinogenic agent that induce malignant transforma- tion. 2 The carcinogenic agents can be chemical, physical, or biologic, and they produce irreversible changes in the genome of a previously normal cell. Because the effects of initiating agents are irreversible, multiple divided doses may achieve the same effects as single exposures of the same comparable dose or small amounts of highly carcinogenic substances. The cells most susceptible to mutagenic alterations in the genome are those that are actively synthesizing DNA. Promotion involves the induction of unregulated accelerated growth in already initiated cells by various chemicals and growth factors. 2 Promotion is reversible if the promoter substance is removed. Cells that have been irreversibly initiated may be promoted even after long latency periods. The latency period varies with the type of agent, the dosage, and the characteristics of the target cells. Many chemical carcinogens are called com- plete carcinogens because they can initiate and promote neoplastic transformation. Progression is the process whereby tumor cells acquire malignant phenotypic changes. These changes may promote the cell’s ability to proliferate autonomously, invade, or metastasize. They may also destabilize its karyotype. FIGURE 7-9. The processes of initiation, promotion, and progression in the clonal evolution of malignant tumors. Initiation involves the exposure of cells to appropriate doses of a carcinogenic agent; promotion, the unregulated and accelerated growth of the mutated cells; and progression, the acquisition of malignant characteristics by the tumor cells.