The Selective Nature of Metastasis

The issue of whether metastases result from the random survival of cells released from a primary tumor or from the selective growth of specialized tumor subpopulations endowed with metastatic properties is important to our understanding of the metastatic process and to the development of therapeutic modalities against metastatic disease. We have found that the tumor cells populating spontaneous metastases are more metastatic than the cells populating the parent neoplasm, clearly indicating that metastasis is selective and not random. The selective nature of metastasis is a consistent observation, however, only when tumor cells are obtained from spontaneous metastases from mice bearing heterogenous, poorly metastatic tumors. Tumor cells from spontaneous metastases from mice bearing tumors that have been selected for metastatic potential or that are homogeneous (cloned) do not differ significantly in metastatic potential from tumor cells populating the parent tumor. Thus, under some conditions the process of metastasis can appear random. Although tumor cells from different individual metastases may be homogeneous with regard to a metastatic phenotype, they may be heterogeneous with regard to their sensitivity to chemotherapeutic agents. Thus, although metastasis selects for metastatic variants, resulting in the population of metastatic foci with tumor cells endowed with metastatic properties, it does not appear to select for phenotypes irrelevant to the process of metastasis such as sensitivity to therapeutic agents.