TGFbeta1 has been implicated in cell cycle control and carcinogenesis. To address the exact function of TGFbeta1 in skin carcinogenesis in vivo, mice with TGFbeta1 expression targeted to keratinocytes were subjected to long-term chemical carcinogenesis treatment. TGFbeta1 showed biphasic action during multistage skin carcinogenesis, acting early as a tumor suppressor but later enhancing the malignant phenotype. The transgenics were more resistant to induction of benign skin tumors than controls, but the malignant conversion rate was vastly increased. There was also a higher incidence of spindle cell carcinomas, which expressed high levels of endogenous TGFbeta3, suggesting that TGFbeta1 elicits an epithelial-mesenchymal transition in vivo and that TGFbeta3 might be involved in maintenance of the spindle cell phenotype. The action of TGFbeta1 in enhancing malignant progression may mimic its proposed function in modulating epithelial cell plasticity during embryonic development.

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Transforming growth factor-131 (TGF-I~I) is a modulator of cellular proliferation, differentiation, and extracellular matrix deposition. It is a potent epithelial growth inhibitor and can alter the differentiative properties of keratinocytes, in vitro, but little is known about its normal physiological function in the epidermis in vivo. Transgenic mice were generated using a keratin 10 (K10) gene promoter to drive constitutive expression of TGF-~I in the suprabasal keratinocyte compartment. Surprisingly, these mice showed a two-to threefold increase in epidermal DNA labeling index over control mice, in the absence of hyperplasia. The transgene, however, acted in the expected fashion, as a negative regulator of cell growth, when hyperplasia was induced by treatment by 12-tetradecanoyl-phorbol-13-acetate (TPA). Epidermal TGF-[~ type I and II receptor (T~RI and T[~RII) levels were examined in control and transgenic mice during induction of hyperplasia by TPA. Whereas T~RI levels remained relatively constant, T~RII expression was strongly induced in TPA-treated skins, prior to the induction of the growth inhibitory response to TGF-131, and its level of expression correlated with growth sensitivity to TGF-~I in vivo and in vitro. These results suggest that TGF-I$1 and its type II receptor are part of the endogenous homeostatic regulatory machinery of the epidermis.

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The galectins are a family of low molecular weight, calcium-independent mammalian carbohydrate binding proteins that exhibit specificity for beta-galactoside derivatives. We have examined the expression pattern of galectin-3 in the developing mouse embryo by in situ hybridisation and immunohistochemistry. In the embryo proper, galectin-3 message and protein are first detected in notochord, starting from 8.5 days post coitum (dpc), and persist until this structure disappears. Galectin-3 is later found in cartilage primordia and in developing skin from 13.5 dpc. This very restricted and dynamic pattern suggests that galectin-3 may participate in the establishment and/or maintenance of notochord as well as the formation of cartilage and differentiation of skin. Finally, we find that galectin-3, which is identical to the macrophage marker Mac-2, is also expressed in embryonic macrophages. 0 1995 Wiley-Liss, Inc.