Apoptosis mediated by extracellular matrix proteins and p53 prevents full in vitro transformation of human fibroblasts.

3047 Much of our current understanding of the pathogenesis of cancer comes from studies performed in rodent cells and animal tumor models. However, human cells are more resistant to both immortalization and transformation. In fact, the same basic genetic changes required for neoplastic transformation in rodent cells have consistently failed to yield tumorigenic transformants in human cells. This indicates fundamental differences in the biology of human and rodent cells and the need to establish more representative model systems to study human tumorigenesis. Recently, several studies have been undertaken to create experimentally transformed human cancer cells in vitro. We describe a novel set of genes capable of full transformation of human cells involving hTERT, E1A, RasV12 combined with inactivation of p53. Full inactivation of p53 could be substituted by Bcl-2 indicating the key role of apoptotic function of p53 in this model of transformation suppression. Further, microarray analyses of human cells undergoing malignant transformation at different stages have identified p53 downstream targets important for transformation. As a result, we have identified the extracellular matrix proteins, Cyr61/CCN1 and CTGF/CCN2 to be both p53-responsive genes and mediators of p53-dependent transformation. Suppression of either Cyr61/CCN1 or CTGF/CCN2 was able to mimic p53 inactivation, resulting in full transformation of human fibroblasts in vitro. These results demonstrate the development of a new human transformation model system, where apoptosis plays a critical role in tumor suppression and the identification of extracellular matrix proteins that may mediate p53-dependent transformation.