Loss of expression of transforming growth factor β 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 papillomas with an increased risk of malignant conversion. These papillomas arise with limited stimulation by tumor promoters, appear rapidly, and do not regress, suggesting that they differ in growth properties from the majority of benign tumors. The transforming growth factor β (TGF-β) proteins are expressed in the epidermis and are growth inhibitors for mouse keratinocytes in vitro; altered TGF-β expression could influence the growth properties of high-risk papillomas. Normal epidermis, tumor promoter-treated epidermis, and skin papillomas at low risk for malignant conversion express TGF-β1 in the basal cell compartment and TGF-β2 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-β1 and TGF-β2 as soon as they arise; these tumors have up to 40% of the proliferating cells in the suprabasal layers. Squamous cell carcinomas are also devoid of TGF-β, suggesting that they arise from the TGF-β-deficient high-risk papillomas. In some high-risk papillomas, TGF-β1 loss can occur first and correlates with basal cell hyperproliferation, while TGF-β2 loss correlates with suprabasal hyperproliferation. Similarly, TGF-β1-null transgenic mice, which express wild-type levels of TGF-β2 in epidermis but no TGF-β1 in the basal layer, have a hyperproliferative basal cell layer without suprabasal proliferation. In tumors, loss of TGF-β is controlled at the posttranscriptional level and is associated with expression of keratin 13, a documented marker of malignant progression. These results show that TGF-β expression and function are compartmentalized in epidermis and epidermal tumors and that loss of TGF-β is an early, biologically relevant risk factor for malignant progression.