Origin of cancer metastases and its implications for therapy.

The process of cancer metastasis is sequential and selective and contains stochastic elements. The growth of metastases represents the endpoint of many lethal events that few tumor cells can survive. Primary tumors consist of multiple subpopulations of cells with heterogeneous metastatic properties, cells whose successful metastasis depends on their interplay with various host factors. Cancer metastases can have a clonal origin, and different metastases can originate from different progenitor cells. Biologic diversity, however, is rapidly generated within metastases and, therefore, their eradication requires the use of multiple therapies early in the course of the disease, even when clear evidence of residual tumor is lacking. The design of specific antimetastatic therapies is dependent on a sound understanding of the biology of metastasis. The clinical challenge presented by neoplastic heterogeneity, especially as it affects metastasis and sensitivity to therapeutic agents, may appear insurmountable. However, it is important to remember that the process of metastasis is regulated by certain mechanisms that can be studied and hopefully understood. The recent increase in our understanding of the processes of tumor progression and metastasis should, therefore, provide important leads for developing more effective approaches for the treatment of disseminated cancer.