Porth's Essentials of Pathophysiology, 4e

137

Neoplasia

C h a p t e r 7

cyclin-dependent proteins), and inhibitors of apoptosis. The category of cancer-associated underactivity genes includes the tumor-suppressor genes , which, by being less active, create an environment in which cancer is promoted. Genetic Events Leading to Oncogene Formation or Activation. There are a number of genetic events that can cause or activate oncogenes. 16 A common event is a point mutation in which there is a single nucleotide base change due to an insertion, deletion, or substitu- tion. An example of an oncogene caused by point muta- tions is the ras oncogene, which has been found in many cancers. 2 Members of the ras proto-oncogene family are important signal-relaying proteins that transmit growth signals to the cell nucleus. Hence, activation of the ras oncogene can increase cell proliferation. Chromosomal translocations have traditionally been associated with cancers such as Burkitt lymphoma and chronic myeloid leukemia. In Burkitt lymphoma the c-myc gene, which encodes a growth signal protein, is translocated from its normal position on chromo- some 8 to chromosome 14, placing it at the site of an immunoglobulin gene. 2 The outcome of the transloca- tion in chronic myeloid leukemia is the appearance of the so-called Philadelphia chromosome involving chro- mosomes 9 and 22 and the formation of an abnormal fusion protein that promotes cell proliferation 3 (see Chapter 11, Fig. 11-6). Recent advances in biotechnol- ogy and genomics are enabling the identification and increased understanding of how gene translocations, even within the same chromosome, contribute to the development of cancer. Another genetic event that is common in cancer is gene amplification. Multiple copies of certain genes may cause overexpression with higher than normal levels of proteins that increase cell proliferation. For example, the human epidermal growth factor receptor-2 (HER-2/neu) gene is amplified in up to 30% of breast cancers and indicates a tumor that is aggressive with a poor prognosis. 17 One of the agents used in treat- ment of HER-2/neu overexpressing breast cancers is trastuzumab (Herceptin), a monoclonal antibody that selectively binds to HER-2, thereby inhibiting the prolif- eration of tumor cells that overexpress HER-2. Genetic Events Leading toLoss of Tumor-Suppressor Gene Function. Normal cells have regulatory genetic mechanisms that protect them against activated or newly acquired oncogenes. These genes are called tumor-suppressor genes. When this type of gene is inactivated, a genetic signal that normally inhibits cell proliferation is removed, thereby causing unregulated growth to begin. 2,3 Mutations in tumor-suppressor genes are generally reces- sive, in that cells tend to behave normally until there is homologous deletion, inactivation, or silencing of both the maternal and paternal genes. Two of the best-known tumor-suppressor genes are the p53 and retinoblastoma (RB) genes. The p53 gene, named after the molecular weight of the protein it encodes, is the most common target for genetic alteration in

Etiology of Cancer The cause or causes of cancer can be viewed from two perspectives: (1) the genetic and molecular mechanisms that characterize the transformation of normal cells into cancer cells and (2) the external and more contextual factors such as age, heredity, and environmental agents that contribute to its development and progression. Together, both mechanisms contribute to a multidimen- sional web of causation by which cancers develop and progress over time. The pathogenesis of most cancers is thought to originate from genetic damage or mutation with resultant changes that transform a normally functioning cell into a cancer cell. Epigenetic factors that involve silencing of a gene or genes may also be involved. In recent years, the role of cancer stem cells in the pathogenesis of cancer has been identified. Finally, the cellular microenvironment that involves the extracellular matrix and a complex milieu of cytokines, growth factors, and other cell types is also recognized as an important contributor to cancer devel- opment and its growth and progression. Cancer-Associated Genes Most cancer-associated genes can be classified into two broad categories based on whether gene overactiv- ity or underactivity increases the risk for cancer. The category associated with gene overactivity involves proto-oncogenes, which are normal genes that become cancer-causing genes if mutated. 2,3 Proto-oncogenes encode for normal cell proteins such as growth fac- tors, growth factor receptors, transcription factors that promote cell growth, cell cycle proteins (cyclins or Genetic and Molecular Basis of Cancer ■■ The spread of cancer occurs through three pathways: direct invasion and extension, seeding of cancer cells in body cavities, and metastatic spread through lymphatic or vascular pathways. Only a proportionately small clone of cancer cells is capable of metastasis.To metastasize, a cancer cell must be able to break loose from the primary tumor, invade the surrounding extracellular matrix, gain access to a blood vessel, survive its passage in the bloodstream, emerge from the bloodstream at a favorable location, and invade the surrounding tissue. Once in the distant tissue site, the metastatic process depends on the establishment of blood vessels and specific growth factors that promote proliferation of the tumor cells.