Metastatic Process Does Not Select Cells for Metastatic Ability But Metastatic Cells Are Selected for by Drug Resistance. Implications for Tumor Progression

Abstract

It is now widely accepted that most tumors consist of subpopulations of cells that differ in many properties, including the ability to give rise to metastases (Fidler and Kripke, 1977). This cellular diversity is acquired during a tumor’s progression towards malignancy. The metastatic potential of a tumor is related to the frequency of tumor cells capable of accomplishing the totality of a very complex process, consisting of sequential steps. A metastatic cell is defined as a tumor cell that has proceeded through the entirety of the metastatic process, invading the surrounding normal tissues, surviving in the lymphatic or blood circulation, stopping and adhering to the capillary vessels and, finally, proliferating in an organ distant from the primary tumor and unrelated to its histological origin. Although it is not possible to exclude the role of stochastic events in the formation of metastases (Weiss, 1985), numerous observations lead one to assume that only a very limited subpopulation of tumor cells undergoes the metastatic process. Such cells could already be present when the tumor is first detectable clinically, suggesting that a subpopulation thus defined pre-exists in the tumor. They could also be constantly generated from non-metastatic tumor cells according to their mutation rate, as demonstrated by Ling et al. (1984). On the basis of these assumptions, the frequency of metastatic cells in a given tumor should be defined and stable, and the metastatic potential of the tumor should be constant.