The refractory nature of colon cancer necessitates the development of new approaches towards this malignant disease. The hallmark of malignant transformation is the loss of normal growth control. Transforming growth factors (TGF-Bs - B1 and B2), a family of small hormone-like polypeptides are potent regulators of growth and differentiation in a variety of normal and tumor derived epithelial cells. Human colon cancer cells are known to produce TGF-B like molecules. However, the biological role of these molecules in colon cancer is unknown. We have developed a human colon cancer cell model which consists of cells that are highly sensitive or resistant to growth inhibition exerted by TGF-Bs, and cells that are selectively sensitive or resistant to growth inhibition exerted by TGF-B1 or B2. The development of this cell model and the identification of additional biochemical responses to TGF-Bs that are distinct from growth inhibition, i.e., cells that are resistant to growth inhibition exerted by TGF-Bs are responding by these criteria, have made it possible to study the mechanisms of responsiveness or selective responsiveness of colon cancer cells to TGF-Bs both the receptor and other cellular level.
The Specific Aims of this project, using this cell model system, are designed to fulfill the following goals: (1), assess if the magnitude of a response or selective response to TGF-B1 or B2 can be accounted for at the receptor level, i.e., in terms of the quantity and/or quality of the TGF-B family of receptors; (2), better define the biological role of TGF-Bs in colon cancer by characterizing other biochemical criteria of responsiveness in addition to growth inhibition and (3), identify other mechanisms that are distal to receptors which may be involved in the magnitude of a response or the types of responses to TGF-B1 and/or B2. Future long-term goals of the research may exploit the leads provided by these studies in the therapeutic intervention of abnormal growth control in colon cancer.
