PRINCIPLES OF TOXICOLOGY - Biology East Borneo

13.4 MOLECULAR ASPECTS OF CARCINOGENESIS 283protooncogenes that commonly occur in human tumors include point mutation, gene rearrangement,gene amplification, chromosomal translocation, and increased transcription (Table 13.6).Tumor Suppressor GenesDemonstration of the existence of cellular oncogenes and knowledge of their function as positiveregulators of cell growth provided an obvious mechanism by which chemicals could induce thecarcinogenic process. The thinking was that an activated oncogene could force the cell and itsdescendants into unneeded rounds of division ultimately resulting in a tumor. However, there was aproblem with such a simplistic view. Researchers soon demonstrated that when tumor cells were fusedwith normal cells, the resulting hybrid cells were usually nontumorigenic. Thus the transforming abilityof oncogenes could be reversed or controlled by some other factor produced by normal cells. It waseventually discovered that normal cells carried genes that coded for proteins that function as negativeregulators of cell growth. These genes came to be called tumor suppressor genes. There now existsmuch evidence supporting the existence of tumor suppressor genes and their functions as negativeregulators of cell growth. To date, approximately 20 putative tumor suppressor genes have beenidentified, although, for many of these, a function is not well understood. Like the oncogenes, theproducts of tumor suppressor genes appear to have diverse functions within the cell. These functionsinclude cell cycle control, transcriptional regulation, regulation of signal transduction, maintenance ofcellular structure, and DNA repair. Some tumor suppressor genes and the functions of the proteins theyencode are shown in Table 13.7. In contrast to the situation with oncogenes where a mutation in onlyone allele is often transforming, the inactivation of tumor suppressor genes requires two genetic events,that is, the inactivation of both alleles. The mechanism most commonly invoked in tumorigenesis is amutation in one allele followed by a subsequent deletion of the second allele or replacement of thesecond allele with a copy of the mutated allele, resulting in what is commonly known as loss ofheterozygosity (LOH).Tumor suppressor genes are often linked to rare, inherited forms of cancer. In fact, the existenceof tumor suppressor genes had been suggested as early as 1971 when Knudson forwarded the “twohit” hypothesis, in which he proposed that the development of retinoblastoma, a rare tumor of the eyein children, required two genetic events. His work eventually led to the cloning of the retinoblastomaTABLE 13.6 Oncogenes Activated in Human TumorsOncogene Neoplasm(s) Lesionabl Chronic myelogenous leukemia TranslocationerbB-1 Squamous cell carcinoma; astrocytoma AmplificationerbB-2 (neu) Adenocarcinoma of the breast, ovary, and stomach Amplificationgip Adenocarcinoma of the ovary and adrenal gland Point mutationsgsp Thyroid carcinoma Point mutationsmyc Burkitt’s lymphoma TranslocationCarcinoma of lung, breast, and cervixAmplificationL-myc Carcinoma of lung AmplificationN-myc Neuroblastoma, small cell carcinoma of lung AmplificationH-ras Carcinoma of colon, lung, and pancreas; melanoma Point mutationsK-rasAcute myelogenous and lymphoblastic leukemia; thyroid Point mutationscarcinoma, melanomaN-rasCarcinoma of the genitourinary tract and thyroid; Point mutationsmelanomaret Thyroid carcinoma RearrangementK-sam Carcinoma of stomach Amplificationtrk Thyroid carcinoma Rearrangement