Coincidental Acquisition of Growth Autonomy and Metastatic Potential During the Malignant Transformation of Factor-Dependent CCL39 Lung Fibroblasts

Abstract

After sc implantation into BALB/c nude mice, factor-dependent and premalignant Chinese hamster lung fibroblasts (CCL39) developed into tumors that occasionally disseminated and produced pulmonary metas-tases. Unlike CCL39 cells that required several growth factors (insulin, α-thrombin, epidermal growth factor) to proliferate in culture, metastatic tumor cells divided autonomously in serum-free medium. The re-implantation of independently isolated primary tumors revealed that they comprised factor-independent clones present at a variable frequency, as well as malignant clones that disseminated to the lungs after sc or iv inoculation. The resulting metastases invariably contained cells that were able to divide in serum-free medium and that presumably represented the progeny of autonomous variants populating the primary tumors. Among ten CCL39 variants selected in vitro for reduced growth factor requirements, two were metastatic upon sc and iv inoculation. These cell lines were the only ones that replicated rapidly in the absence of growth factors. Unlike myc transfectants, CCL39 fibroblasts that were transformed with an activated Harvey ras oncogene or that were infected with polyomavirus were both metastatic and autonomous. Taken together, these observations are consistent with the notion that the metastatic potential of CCL39 tumor cells coincides with their ability to obviate growth factor requirements and thus to divide in an autonomous fashion.