Mechanism of carcinogenesis: the role of oncogenes, transcriptional enhancers and growth factors.

The oncogenes are a set of genes that have been implicated as the basis of cancer. They are the activated forms of proto-oncogenes which are part of the genetic complement of all normal cells. Activation can result from mutations in the global sense i.e. point mutations, nucleotide deletions or insertions, and chromosomal translocations. These mutations induce quantitative or qualitative changes in oncogene expression. Several human oncogenes identified in tumors and established cell lines have been cloned and studied in great detail using gene transfer techniques. Evidence has accumulated supporting the view that a single oncogene can be involved at different stages or steps in a multi-stage carcinogenesis process. Moreover, a single properly activated oncogene can trigger the whole process of malignant conversion of a normal cell. Thus both the one gene--one cancer and the multigene--one cancer hypotheses may be correct. The most frequently activated oncogenes in tumors detected by the NIH3T3 assay belong to the ras family. These ras genes code for a membrane bound protein (ras p21) which has a GTPase activity. The ras p21 encoded by the T24 activated form of the Ha-ras1 oncogene has an impaired GTPase activity. In view of the location of ras p21 and its biological effects it is proposed that the action of p21 is regulated by growth factors through their membrane receptors. Transcriptional enhancers are cis-acting positive regulatory DNA elements present in viral and cellular genomes. Their involvement in the development of certain types of cancer has been strongly suggested from studies with viruses and chromosome translocations. The in vitro construction of genetic hybrids linking viral transcriptional enhancers and cloned human oncogenes, and the subsequent transformation of early passage cells has been helpful in delineating stages in the malignant conversion of normal cells and gaining insights into the mechanism of carcinogenesis. Transforming growth factors (TGFs) are low molecular weight proteins that reversibly induce anchorage independent growth of certain cells such as the NRK cells. At least two types of TGFs, alpha and beta have been identified. Introduction and expression of cloned human Ha-ras genes in mammalian cells trigger TGF release into the medium. This can occur both in stable transformants and in cells shortly after transfection. The latter suggests that TGF release by the transfected cell is the direct result of the oncogene action rather than a consequence of a cellular change during the process of transformation.(ABSTRACT TRUNCATED AT 400 WORDS)