MODULATION OF CELLULAR PROLIFERATION BY EPIDERMAL GROWTH FACTOR AND RELATED POLYPEPTIDES.

Epidermal growth factor (EGF) markedly stimulates cell proliferation in a variety of mammalian systems. For this reason, EGF and factors related to EGF were examined for a possible role in the promotion and maintenance of the uncontrolled growth state that is a characteristic of malignant neoplasias. Phorbol ester tumor promoters, compounds that are capable of promoting tumors in the mouse skin carcinogenesis assay, act synergistically with EGF to stimulate DNA synthesis in cultured fibroblasts despite an inhibitory effect on the binding of EGF to its cellular receptor. Sparing of EGF degradation in combination with recovery of EGF binding was postulated to be responsible for the increased role of DNA synthesis in cells exposed to the phorbol esters. The hypothesis is presented that the hyperplasiogenic component of tumor promotion may be mediated, at least in part, by local alterations in growth factor levels. Recent evidence suggests the existance of a family of molecules related to EGF as defined by the ability to bind to the EGF receptor. These factors (transforming growth factors) appear to be responsible for the phenotypic alterations characteristic of transformed cells. Using a radioreceptor assay, two EGF-like factors were isolated from mouse submaxillary gland. These factors were not transforming growth factors and appeared to be modified EGF molecules. Two EGF-like factors, molecular weight 27,000 and 13,000, were identified in medium conditioned by Rous sarcoma virus (RSV)-transformed cells and were shown to possess the characteristics of a transforming growth factor. In addition, rat fetus extracts contained a 55,000 molecular weight EGF-like factor with the properties of a transforming growth factor. The EGF-effector system may therefore play an important role in embryonic development and in the maintenance of the neoplastic phenotype. The difference in the molecular weights of the RSV-factor and the fetus factor indicates that there are numerous members of the class of EGF-like molecules, and that RSV-transformation probably does not induce the re-expression of a fetal growth stimulatory factor. The results of these experiments suggest that EGF and EGF-like factors are biologically important growth-stimulating molecules that must be tightly regulated to maintain normal physiological conditions