Pathologic alteration of the response of colon epithelium to TGF-beta's negative autocrine action plays a key role in colon cancer progression. The applicant has demonstrated: (1) that reduction of TGF-beta response is associated with the transformation of human colon adenoma cells to the malignant state; (2) loss of TGF-beta response is associated with a high degree of progression in human colon cancer cell lines, and (3) repression of autocrine negative TGF-beta activity in human colon cancer cells results in an increase in tumorigenicity. The analysis of the cellular mechanisms underlying TGF-beta pathology will identify potential targets for restoring normal growth factor balance; however, the eventual application of therapeutic strategies will depend upon a mechanistic understanding of how TGF-beta operates in vivo. To address this issue, the applicant has developed unique xenograft models designed to disrupt either TGF-beta autocrine negative growth factor activity or TGF-beta paracrine effects on host tissue by modulation of growth factors or receptors. In this application, he proposes to use these xenograft models to determine the mechanistic bases for tumor growth or lack of tumor growth in vivo. The experimental plan will address four hypothetical bases for the role of the TGF-beta produced by colon carcinoma cells in malignant progression. These are: (1) Tumor cell TGF-beta acts as an overall repressor of angiogenesis in well- differentiated poorly tumorigenic cells with a low level of progression. (2) Autocrine TGF-beta activity is a negative determinant of malignant cell proliferation, but enhances the apoptotic fraction of malignant cells in well-differentiated tumors. (3) TGF-beta suppresses positive growth factor expression in early malignant cells. (4) TGF-beta is a determinant of extracellular matrix expression (ECM) in both tumor and stromal cell compartments in vivo.
