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Blocking Transforming Growth Factor ß Signaling in Transgenic Epidermis Accelerates Chemical Carcinogenesis

A Mechanism Associated with Increased Angiogenesis¹

Departments of Otolaryngology [C. G.], Cell Biology [P. L., X-J. W.], and Dermatology [X-J. W.], Baylor College of Medicine, Houston, Texas 77030

Mutations in the transforming growth factor ß type II receptor (TGF-ßRII) have been identified in human cancers, which suggests a causal role for the loss of TGF-ßRII in cancer development. To directly test this in vivo, we have generated transgenic mice expressing a dominant negative TGF-ßRII (ßRII) in the epidermis, using a truncated mouse loricrin promoter (ML). ML.ßRII transgenic mice exhibited a thickened skin due to epidermal hyperproliferation. When these mice were subjected to a standard two-stage chemical carcinogenesis protocol, they exhibited an increased sensitivity, with an earlier appearance and a 2-fold greater number of papillomas than control mice. In addition, papillomas in control mice regressed after termination of 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment; whereas ML.ßRII papillomas progressed to carcinomas. Furthermore, TPA promotion alone induced papilloma formation in ML.ßRII mice, which suggests an initiating role for ßRII in skin carcinogenesis. ML.ßRII tumors also exhibited increased neovascularization and progressed to metastases, although the primary tumors were still classified as carcinoma in situ or well-differentiated carcinomas. Increased expression of vascular endothelial growth factor, an angiogenesis factor, and decreased expression of thrombospondin-1, an angiogenesis inhibitor, were also observed in ML.ßRII tumors. The increased angiogenesis correlated with elevated endogenous TGF-ß1 in ML.ßRII tumors. These data provide in vivo evidence that inactivation of TGF-ßRII accelerates skin carcinogenesis at both earlier and later stages, and increased angiogenesis is one of the important mechanisms of accelerated tumor growth and metastasis.

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