DIFFERENTIAL CONTROL BY PLATELET FACTORS OF SQUAMOUS DIFFERENTIATION IN NORMAL AND MALIGNANT HUMAN BRONCHIAL EPITHELIAL-CELLS

Abstract

A nutritionally optimal medium for rapid clonal growth (> 1 population doubling/day) of normal human bronchial epithelial (NHBE) cells was developed. Adding fetal bovine or adult human blood-derived serum to this medium depresses the clonal growth rate of NHBE cells in a dose-dependent fashion. In contrast, 10 representative lines of human lung carcinomas either duplicate poorly or fail to grow at all when inoculated at clonal density in serum-free medium, and their rates of multiplication increase in direct proportion to the amount of blood-divided serum added to the optimized medium. Thus, the growth factor requirements of these lung carcinoma cell lines are significantly different from those of their normal counterparts. Blood-divided serum reduces the clonal growth rate of NHBE cells by specifically inducing the normal cells, but not lung carcinoma cells, to undergo squamous differentiation. The differentiation-inducing activity was found in platelet lysates. In addition, a growth-inhibiting activity that did not induce squamous differentiation of NHBE cells was also identified in partially purified commercial preparations of platelet-derived growth factor. This observation was in marked contrast to results using human bronchial fibroblasts and human lung carcinoma cell lines; the growth rate of the former was significantly stimulated by commercial preparations of platelet-derived growth factor, whereas the growth rates of the tumor cell lines were unaffected. An aberration in the cellular differentiation as assayed in vitro apparently is positively correlated with cancer. Decreased responsiveness to inducer(s) of differentiation may be a major aspect of bronchial cell carcinogenesis.