Employing unique cell and xenograft models, pathological alterations in growth factor responses were demonstrated to play key roles in colon cancer progression. Using a tetracycline repressible expression system in colon cancer xenograft models, loss of TGF beta signaling was linked to colon cancer progression and restoration of TGF beta signaling reversed tumorigenicity. In a second line of investigation, ectopic expression of TGF alpha resulted in accelerated tumor growth and tetracycline mediated reversal of this ectopic expression caused tumors to regress. At the inception of the studies, it was anticipated that the primary consequence of disrupted growth factor signaling in these colon cancer xenograft models would be a direct alteration in growth regulation at the cell cycle level. Unexpectedly, the results suggest that the altered tumor growth was largely due to modulation of extracellular components of the xenograft such as integrin expression or angiogenesis and that these changes in turn appear to have dramatic effects on in vivo tumor cell proliferation or apoptosis. These results suggest that tumor progression involves autocrine growth factor controlled interactions of malignant cells with the tumor microenvironment to prevent or treat colon cancers. To examine the role of candidate autocrine activities in human colon cancer progression, in vivo models which will confirm the dependency of tumor growth on these autocrine activities by modulating downstream effectors of their action are planned. Candidate molecular targets will be modulated in vivo using tetracycline controllable systems. A central issue which the applicant will examine is the relationship of tumor stage on the impact of growth factor modulation. For the purposes of these studies, he plans to evaluate xenograft tumors at two different stages, the dormant phase or pre-angiogenic phase of growth and the growth phase or post """"""""angiogenic switch"""""""" phase. By linking the expression of a specific molecular mechanism (e.g. elevated angiogenesis due to malignant cell VEGF expression) to a tetracycline responsive promotor, he can examine the impact of modulating that mechanism in vivo at these two stages of xenograft tumor progression. The ultimate goal of this proposed investigation is to use the unique human colon cancer xenograft models that will be developed to evaluate new pharmaceutical agents designed to target novel molecular mechanisms of tumor progression.
