Retinoic acid restores shape-dependent growth control in neoplastic cells cultured on poly(2-hydroxyethyl...

The ability of retinoic acid to modulate cell-shape-dependent growth of untransformed (human skin fibroblasts and mouse embryo Swiss 3T3 fibroblasts) and neoplastic cells (human cervical carcinoma HeLa-S3, osteosarcoma Hs791, and murine melanomas B16-F1, S91-C2 and S91-C154) was examined. The cells were plated on tissue culture dishes coated with increasing concentrations of poly(2-hydroxyethyl methacrylate), poly(HEMA) which cause a gradual decrease in substrate adhesiveness. Untreated cells as well as cells pretreated with 10 microM retinoic acid for 4 days displayed a similar graded series of cell shapes between flat and spherical on these modified substrata, with the exception of HeLa-S3 cells which were rounded and loosely attached even on uncoated plastic dishes. A marked cell-shape-dependent decrease in DNA synthesis was observed in untransformed human skin fibroblasts, Swiss 3T3 fibroblasts and neoplastic human Hs791 cells 20 h following plating of untreated cells on poly(HEMA)-coated substrates of decreasing adhesiveness. Conversely, in B16-F1, HeLa-S3 and S91-C154 cells DNA synthesis was only slightly affected by changes in cell shape. Pretreatment with retinoic acid rendered DNA synthesis in Swiss 3T3, Hs791, B16-F1 and S91-C2 cells much more sensitive to changes in cell shape. In contrast, retinoic acid exerted only marginal effects on the sensitivity of DNA synthesis to changes in cell shape in untransformed human skin fibroblasts, in HeLa-S3 cells and in the retinoic-acid-resistant S91-C154 cells. The results suggest that retinoic acid can restore in certain tumor cells the tight coupling between cell shape and DNA synthesis that exists in untransformed cells.