Transforming growth factor-bs (TGF-bs) are potent inhibitors of epithelial cell growth. Recently components of the TGF-b response path have been shown to be diminished or absent in a number of human malignancies, implicating loss of TGF-b function as one mechanism contributing to tumor development. However, TGF-b ligand expression is often upregulated in advanced human cancers suggesting that the role played by the TGF-b system may be complex. We and others have proposed that TGF-bs function as tumor suppressors early in the tumorigenic process and as pro-metastatic agents in late-stage disease. Understanding the complex biology of TGF-b in cancer progression will be critical for effective therapeutic targeting of the TGF-b system. Since the effects of TGF-b are highly context-dependent, where possible we have chosen to study the biology of this system in vivo in the whole animal, so that all the complex contextual cues are maintained. Our approach has been to generate and analyze genetically engineered mice in which TGF-b function is experimentally compromised. In a complementary approach, we genetically modify TGF-b function in cell lines and determine the effect on tumorigenicity by xenografting these into nude mice. We focus particularly on breast cancer. Using a series of human breast-derived cell lines representing different stages of the tumorigenic process we have demonstrated that TGF-bs do indeed switch from tumor suppressor to pro-metastatic factors in the late stages of breast cancer. We are exploiting this model system to analyze the biological and molecular mechanisms that underlie the """"""""metastatic switch"""""""". To address whether neutralization of TGF-b might be a useful therapeutic approach for advanced cancer, we have generated transgenic mice expressing a protein TGF-b antagonist, and we have shown that these mice are significantly protected against metastasis. Unexpectedly, there were essentially no adverse side effects of TGF-b antagonist treatment, so we are currently pushing this approach through further pre-clinical development. Finally, we are addressing the question of whether the tumor suppressor and pro-metastatic activities of TGF-b are mediated by distinct signaling pathways. To do this, we are working with mammary epithelial cells derived from mice in which different Smad components of the TGF-b signal transduction pathway have been genetically knocked out. Results from all these experiments should give clinically useful insights into the functions of TGF-bs during tumor initiation, promotion and progression, and illuminate how the system could be most effectively manipulated in novel chemopreventive or therapeutic strategies.
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