The evolution of diversity within tumors and metastases

The metastatic process is a series of steps – each of which must be completed for the development of a metastatic focus. Some steps consist of stochastic elements; however, overall the process selects for cellular phenotype(s) with metastatic properties from the heterogeneous cellular populations that develop within the primary tumor. Thus, although individual metastases are of clonal origin, different metastatic foci can originate from cellular variants. The development of cellular diversity is not a process unique to tumor cells. Cellular diversity rapidly evolves due to the genetic instability of metastatic cells, the selective pressures of the metastatic process and clinical interventions, and interactions with the microenvironment, including cellular immunity and tissue and organ microenvironments that can facilitate or suppress tumor growth, metastasis, and tumor cell survival. It is the cellular heterogeneity within the primary tumor, between metastatic foci, and within individual metastatic foci that provides a significant challenge for oncologists for successful clinical intervention.