TARGETED DELETION OF THE TGF-BETA-1 GENE CAUSES RAPID PROGRESSION TO SQUAMOUS-CELL CARCINOMA

To study the contribution of autocrine and paracrine TGE-beta 1 to tum or progression in a well-defined system of multistage carcinogenesis, keratinocytes with a targeted deletion of the TGF-beta 1 gene were ini tiated in vitro with the v-ras(Ha) oncogene and their in vivo tumorige nic properties were determined by skin grafting initiated cells onto a thymic mice in combination with either wild-type or null dermal fibrob lasts. Grafts of v-ras(Ha)-initiated null keratinocytes progressed rap idly to multifocal squamous cell carcinomas within dysplastic papillom as irrespective of the fibroblast genotype, whereas the initiated cont rol genotypes formed well-differentiated papillomas. Malignant progres sion was not associated with mutations in the c-ras(Ha) gene, alterati ons in p53 protein, or loss of responsiveness to TGF-beta 1. The tumor cell labeling index was elevated in grafts of initiated null keratino cytes with wild-type fibroblasts compared to tumors of other genotypes . However, labeling index in all tumors was reduced when TGF-beta 1 nu ll fibroblasts formed the stroma. The null tumor cells could not accum ulate TGE-beta 1 from the host, but grafts of uninitiated null keratin ocytes, which formed a normal epidermis, became TGE-beta 1 positive ev en though they did not express TGF-beta 1 mRNA. These results demonstr ate that autocrine TGF-beta 1 suppresses the frequency and rate of mal ignant progression, and that autocrine and paracrine TGF-beta 1 can ha ve opposing effects on tumor cell proliferation. The lack of paracrine inhibition of tumor tell progression appears to result from the inabi lity of tumor cells to localize host-derived TGF-beta 1 by a mechanism that operates in normal cells.