Role of oncogenes in metastases

The mechanisms responsible for the induction of metastatic behavior in tumor cells have yet to be fully elucidated. A number of intriguing hypotheses have been put forward, but have not been confirmed. All depend on the observation that the ability to metastasize is not the same in all cells within a tumor, but varies markedly between cells within a tumor leading to the placement of metastasis within the general phenomenon of tumor heterogeneity (1,2). Some of these models assume that genetic alterations in the cell lead to metastasis, while others are based upon non-heritable fluctuations. Weiss (3) has long espoused models in which cells subject to as yet undefined environmental influences can transiently acquire the ability to metastasize. The most prominent model for tumor progression based on genetic events is that of Nowell (4) who had proposed that tumorigenic cells have an increased frequency of mutation and that these mutations are required to induce metastasis. While on first appearance, these models may seem to be contradictory, in fact both mechanisms might operate. For example, the genetic change could lead to the ability to respond to an external factor which then induces metastasis. Since only a small fraction of cells injected into a mouse or tested in an in vitro assay eventually metastasize, such a synthesis of the two models is appealing. Until recently, it has not been possible to systematically induce metastatic behavior in cells. However, as will be detailed below, the ras oncogene can serve such a function. While it is consistent with the genetic hypothesis that the introduction of an activated oncogene could lead to metastasis, this finding does not resolve the issue as to the extent of importance of environmental factors and in no way proves that genetic alterations lead to metastasis in actual human tumors.