Transforming growth factor β1 enhances tumor promotion in mouse skin carcinogenesis

Transforming growth factor b1 (TGFβ1) expression is elevated by tumor promoters in the mouse skin, but its role in tumor pro-motion has not been well defined. To investigate this, we have compared TGFβ1+/+ and +/- mice in a two-stage skin chemical carcinogenesis protocol. Surprisingly, TGFβ1+/- mice had fewer number and incidence of benign papillomas, reduced epi-dermal and tumor cell proliferation and reduced epidermal TGFβ1 and nuclear p-Smad2 localization in response to the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) compared with TGFβ1+/+ mice. Maximal TPA activation of protein kinase C (PKCα) as measured by activity assays and activation of target genes and induction of cornified envelopes correlated with TGFb1 gene dosage in keratinocytes and addition of exogenous TGFb1 restored the cornification defect in TGFβ1+/- keratinocytes. Similarly, inhibition of ALK5-suppressed TPA-mediated PKCa activation suggesting that physiological levels of TGFb1 are required for maximal activation of PKC-dependent mitogenic responses. Paradoxically, the TPA-induced inflammatory response was greater in TGFbβ1/+ skin, but TGFβ1+/+ papillomas had more tumor infiltrating myeloperoxidase-positive cells and pro-inflammatory gene expression was elevated in v-ras^Ha-transduced TGFβ1+/+ but not TGFβ1+/- keratinocytes. Thus, ras activation switches TGFβ1 to a pro-inflammatory cytokine. Despite this differential proliferative and inflammatory response to TPA and enhanced papilloma formation in the TGFβ1+/+ mice, the frequency of malignant conversion was reduced compared with TGFβ1+/- mice. Therefore, TGFb1 promotes benign tumors by modifying tumor promoter-induced cell proliferation and inflammation but retains a suppressive function for malignant conversion.