The systemic progression of human cancer: a focus on the individual disseminated cancer cell--the unit of selection.

The metastatic progression of solid tumors is discussed controversially. Because metastasis is usually lethal, it appears as an end point of successive cellular changes. This has led to the prevailing interpretation that genetic changes, in addition to those present in the most advanced clone of the primary tumor, are required to initiate invasion, dissemination, and growth at anatomically distant sites. It has become possible to detect and analyze single disseminated cancer cells at ectopic sites long before metastasis can be diagnosed by standard clinical techniques. Because the finding of single disseminated cancer cells correlates with the subsequent development of distant metastasis, these cells have been identified as the precursors of metastasis. Their direct molecular-genetic characterization, however, shows that dissemination occurs very early in the process of accumulation of genetic changes and suggests that metastases may seldom be derived from the dominant clone of the primary tumor. In contrast, it appears that cancer cell evolution explores a multitude of variant cells from which systemic cancer can develop independently. This review integrates data derived by different approaches into a model of systemic cancer progression.