LOSS OF MATRIX ADHESION TRIGGERS RAPID TRANSFORMATION-SELECTIVE APOPTOSIS IN FIBROBLASTS

Cell-matrix and cell-tell adhesion are recognized physiological determ inants of cell growth and survival. In epithelial and endothelial cell systems, oncogenic transformation has in several cases been shown to confer resistance to apoptosis upon depriving cells of substrate adhes ion. We examined the effects of oncogenic transformation in adherent v ersus adhesion-deprived primary embryonic fibroblasts. Whereas untrans formed early passage fibroblasts undergo cell cycle arrest, their Myc/ Ras- or E1A/Ras-transformed counterparts rapidly enter apoptosis when placed into suspension. This phenomenon also occurs upon incubation wi th a soluble, RGD-containing integrin ligand and is blocked by a pepti de antagonist to ICE family proteases or by aggregation of cells plate d at high density. Loss of wild-type p53 modulates the kinetics but do es not abrogate this death pathway. Transformation with activated Src rather than Ras rendered fibroblasts selectively resistant to adhesion -dependent apoptosis, an effect likely related to Src's role in integr in signaling, while simultaneously sensitizing the cells to radiation- induced apoptosis. Thus cell adhesion events regulate transformation-s elective apoptosis in fibroblasts and provide potentially important ta rgets for understanding and interfering with tumor cell viability.