Porth's Essentials of Pathophysiology, 4e

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Neoplasia

C h a p t e r 7

anti-apoptotic protein that protects tumor cells from apoptosis. Molecular and Cellular Pathways Numerous molecular and cellular mechanisms with a myriad of associated pathways and genes are known or suspected to facilitate the development of cancer. These mechanisms include defects in DNA repair mechanisms, disorders in growth factor signaling pathways, evasion of apoptosis, development of sustained angiogenesis, and evasion of metastasis. Mechanisms and genes that regulate repair of dam- aged DNA have been implicated in the process of oncogenesis (Fig. 7-7). The DNA repair genes affect cell proliferation and survival indirectly through their ability to repair nonlethal damage in other genes including proto-oncogenes, tumor-suppressor genes, and the genes that control apoptosis. 2.3 These genes have been implicated as the principal targets of genetic damage occurring during the development of a can- cer cell. Such genetic damage may be caused by the action of chemicals, radiation, or viruses, or it may be inherited in the germ line. Significantly, it appears that the acquisition of a single-gene mutation is not sufficient to transform normal cells into cancer cells.

Instead, cancerous transformation appears to require the activation of many independently mutated genes. A relatively common pathway by which cancer cells gain autonomous growth is by mutations in genes that control signaling pathways between growth fac- tor receptors on the cell membrane and their targets in the cell nucleus. 2 Under normal conditions, cell prolif- eration involves the binding of a growth factor to its receptor on the cell membrane, activation of the growth factor receptor on the inner surface of the cell mem- brane, transfer of the signal across the cytosol to the nucleus via signal-transducing proteins that function as second messengers, induction and activation of regula- tory factors that initiate DNA transcription, and entry of the cell into the cell cycle (Fig. 7-8). Many of the pro- teins involved in the signaling pathways that control the action of growth factors in cancer cells exert their effects through enzymes called kinases that phosphorylate pro- teins. In some types of cancer such as chronic myeloid leukemia, mutation in a proto-oncogene controlling tyrosine kinase activity occurs, causing unregulated cell growth and proliferation.

Growth factor

Outer cell membrane

Growth factor receptor

Carcinogenic agent

Normal cell

DNA repair (DNA repair genes)

Inactive

Active

Inner cell membrane

Activation

DNA damage

Failure of DNA repair

Signal- tranducing proteins

P

• Activation of growth-promoting oncogenes • Inactivation of tumor-suppressor genes • Alterations in genes that control apoptosis

P

MAP kinase

P

Unregulated cell differentiation and growth

Activation of transcriptase

P

MAP kinase

P

Nucleus

P

Malignant neoplasm

FIGURE 7-8. Pathway for genes regulating cell growth and replication. Stimulation of a normal cell by a growth factor results in activation of the growth factor receptor and signaling proteins that transmit the growth-promoting signal to the nucleus, where it modulates gene transcription and progression through the cell cycle. Many of these signaling proteins exert their effects through enzymes called kinases that phosphorylate (P) proteins. MAP, mitogen-activating protein.

FIGURE 7-7. Flow chart depicting the stages in the development of a malignant neoplasm resulting from exposure to an oncogenic agent that produces DNA damage. When DNA repair genes are present (red arrow), the DNA is repaired and gene mutation does not occur.