Apoptosis is inversely related to necrosis and determines net growth in tumors bearing constitutively expressed myc, ras, and HPV oncogenes

Abstract

Immortalized rat fibroblasts were transfected with expression plasmids containing a mutated human Ha-ras (T24) oncogene, human c-myc, HPV 16 or 18 genomes, or combinations of these. Cell proliferation rates in vitro of the resulting 13 transformed lines were closely similar but apoptotic rates in vitro varied over a 60-fold range and correlated inversely with rates of population expansion in culture. To determine whether such differences in susceptibility to apoptosis affected the pattern of tumor growth in vivo, the transfected lines were injected subcutaneously into immunesuppressed mice producing fibrosarcomas in which prevalence of apoptosis and mitosis, extent of necrosis, and net growth rate were measured. Cell lines with high apoptotic rates in vitro tended to generate slowly growing tumors with high ratios of apoptosis to mitosis and little necrosis. The three most extreme examples of this phenotype all resulted from single transfections with c-myc. Lines with low apoptotic rates in vitro generated rapidly expanding tumors with high mitotic rates, extensive necrosis, and little apoptosis relative to mitosis, even in the compromised zone at the edge of necrotic regions. The four fastest-growing tumors all contained a T24-ras oncogene. The results suggest that oncogene expression determines intrinsic apoptotic rates and in this way may significantly influence the net growth rate and extent of necrosis in tumors.