The origin of metastatic heterogeneity in tumors

These studies were conducted to determine whether the metastatic heterogeneity that is frequently observed in primary neoplasms is a consequence of multicellular transformation or acquired genetic variability. $\text{BALB}\text{c}$ embryo fibroblasts were infected in vitro with mouse sarcoma virus. Six tumor colonies, each derived from a single transformed cell, were isolated and propagated as individual cell lines. Twenty-four days after virus infection, mice were injected s.c. or i.v. with viable cells harvested from the individual lines. Subcutaneous tumors developed in nearly all of the mice and regressed 30 days after inoculation. In contrast, the production of lung tumor colonies varied significantly among the cell lines. Moreover, the individual lines were found to be heterogeneous. This conclusion is based on results of experiments in which two cell lines exhibiting either a low or high propensity to produce lung tumor colonies were subcloned. Cells from these subclones were injected i.v. into syngeneic mice. The subclones differed significantly among themselves and from the parent culture in their ability to produce lung tumor colonies. We conclude that regardless of whether neoplasms are unicellular or multicellular in origin, they can be heterogeneous and contain subpopulations of cells with different metastatic properties by the time of diagnosis.