LOSS OF EXPRESSION OF TRANSFORMING GROWTH-FACTOR-BETA IN SKIN AND SKIN TUMORS IS ASSOCIATED WITH HYPERPROLIFERATION AND A HIGH-RISK FOR MALIGNANT CONVERSION

Mouse skin carcinomas arise from a small subpopulation of benign papil lomas with an increased risk of malignant conversion. These papillomas arise with limited stimulation by tumor promoters, appear rapidly, an d do not regress, suggesting that they differ in growth properties fro m the majority of benign tumors. The transforming growth factor beta ( TGF-beta) proteins are expressed in the epidermis and are growth inhib itors for mouse keratinocytes in vitro; altered TGF-beta expression co uld influence the growth properties of high-risk papillomas. Normal ep idermis, tumor promoter-treated epidermis, and skin papillomas at low risk for malignant conversion express TGF-beta1 in the basal cell comp artment and TGF-beta2 in the suprabasal strata. In low-risk tumors, 90 % of the proliferating cells are confined to the basal compartment. In contrast, the majority of high-risk papillomas are devoid of both TGF -beta1 and TGF-beta2 as soon as they arise; these tumors have up to 40 % of the proliferating cells in the suprabasal layers. Squamous cell c arcinomas are also devoid of TGF-beta, suggesting that they arise from the TGF-beta-deficient high-risk papillomas. In some high-risk papill omas, TGF-beta1 loss can occur first and correlates with basal cell hy perproliferation, while TGF-beta2 loss correlates with suprabasal hype rproliferation. Similarly, TGF-beta1-null transgenic mice, which expre ss wild-type levels of TGF-beta2 in epidermis but no TGF-beta1 in the basal layer, have a hyperproliferative basal cell layer without suprab asal proliferation. In tumors, loss of TGF-beta is controlled at the p osttranscriptional level and is associated with expression of keratin 13, a documented marker of malignant progression. These results show t hat TGF-beta expression and function are compartmentalized in epidermi s and epidermal tumors and that loss of TGF-beta is an early, biologic ally relevant risk factor for malignant progression.