Transforming growth factor β1 enhances tumor promotion in mouse skin carcinogenesis

Transforming growth factor beta 1 (TGF beta 1) expression is elevated by tumor promoters in the mouse skin, but its role in tumor promotion has not been well defined. To investigate this, we have compared TGF beta 1+/+ and +/- mice in a two-stage skin chemical carcinogenesis protocol. Surprisingly, TGF beta 1+/- mice had fewer number and incidence of benign papillomas, reduced epidermal and tumor cell proliferation and reduced epidermal TGF beta 1 and nuclear p-Smad2 localization in response to the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) compared with TGF beta 1+/+ mice. Maximal TPA activation of protein kinase C (PKC alpha) as measured by activity assays and activation of target genes and induction of cornified envelopes correlated with TGF beta 1 gene dosage in keratinocytes and addition of exogenous TGF beta 1 restored the cornification defect in TGF beta 1+/- keratinocytes. Similarly, inhibition of ALK5-suppressed TPA-mediated PKC alpha activation suggesting that physiological levels of TGF beta 1 are required for maximal activation of PKC-dependent mitogenic responses. Paradoxically, the TPA-induced inflammatory response was greater in TGF beta 1+/- skin, but TGF beta 1+/+ papillomas had more tumor infiltrating myeloperoxidase-positive cells and pro-inflammatory gene expression was elevated in v-ras(Ha)-transduced TGF beta 1+/+ but not TGF beta 1+/- keratinocytes. Thus, ras activation switches TGF beta 1 to a pro-inflammatory cytokine. Despite this differential proliferative and inflammatory response to TPA and enhanced papilloma formation in the TGF beta 1+/+ mice, the frequency of malignant conversion was reduced compared with TGF beta 1+/- mice. Therefore, TGF beta 1 promotes benign tumors by modifying tumor promoter-induced cell proliferation and inflammation but retains a suppressive function for malignant conversion.