Polypeptide factors which stimulate or inhibit cell growth have been identified in many normal and neoplastic tissues and cells. We have identified and purified 2 inhibitory peptides called tumor inhibitory factors (TIF) and transforming growth factor-B (TGF-B) from a human colon carcinoma cell line. The long term goals of this project are to understand the mechanisms by which these 3 factors inhibit cell growth. These experiments will utilize two model systems: a bank of human colon carcinoma cell lines which vary in their growth and biological properties and a transformed and nontransformed mouse embryo fibroblast cell line. The level of 2 TIF's and TGF-B produced by color carcinoma cell lines (some of which are responsive and others non-responsive to these factors) will be examined to determine if there is a correlation between the factors produced and the sensitivity of the cells to these factors. The ability of these factors to affect DNA synthesis of the mouse fibroblast cell line will be determined. The effect of differentiation agents on the types of growth factors produced by the colon cells and their ability to induce DNA synthesis in fibroblasts will also be examined. One differentiation agent blocks the induction of DNA synthesis by TGF-B in fibroblasts. In order to determine at which step of the mitogenic cascade this occurs, the effect on TGF-B binding to its receptor and expression of platelet-derived growth factor and its mRNA will be determined. An assay system utilizing the colon carcinoma cell lines will be established to answer similar questions. This project will provide information concerning the mechanism of growth control in normal and malignant cells. This may lead to the design of agents which may be of therapeutic use in halting malignant cell growth.
