EPITHELIAL HOMEOSTASIS AND CARCINOGENESIS IN TGF BETA COMPROMISED MOUSE MODELS

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Transforming growth factor-betas (TGF-betas) are potent inhibitors of epithelial cell growth. Recently the type II TGF-beta receptor has been shown to be diminished or absent in a number of human malignancies, implicating loss of TGF-beta function as one mechanism contributing to tumor development. We have tested the importance of the TGF-beta system in epithelial homeostasis in vivo by generating transgenic animals overexpressing a dominant negative form (DNR) of the type II TGF-beta receptor under the control of the metallothionein (MT) promoter, or the MMTV LTR, in order to knock out response to TGF-beta in select epithelia. In the MT-DNR animals, high level expression of the dominant negative receptor construct in the pancreas results in progressive atrophy of the exocrine pancreas, associated with ductal metaplasia and fatty replacement. Enhanced proliferation of acinar cells is observed, consistent with roles for TGF-betas in limiting proliferation and maintaining structural integrity of the exocrine pancreas. In the liver and mammary glands, no basal phenotype is observed but the mice appear to show enhanced susceptibility to chemical carcinogens, indicating that TGF-betas may normally protect against tumorigenesis in these organs. We see similarly enhanced susceptibility to chemical carcinogens in the lungs and livers of mice with only one TGF-beta1 allele. Furthermore, we are exploring the possible role of TGF-betas in prostatic development and tumorigenesis using retroviral transduction to introduce the DNR into rat prostatic cell lines of varying malignancy, and forming prostatic tissue recombinants with urogenital ridge mesenchyme in nude mice. Results from all these experiments should give clinically useful insights into the physiological functions of TGF-betas during tumor initiation, promotion and progression, and illuminate how the system could be most effectively used in novel chemopreventive strategies.