TGFα stimulates growth of skin papillomas by autocrine and paracrine mechanisms but does not cause neoplastic progression

To investigate the role of transforming growth factor α (TGFα) in tumor development, we introduced the human TGFα (hTGFα) cDNA into cultured primary mouse epidermal cells or papilloma cells using a replication-defective retroviral vector and analyzed skin grafts constructed with such cells. Expression of the exogenous gene was confirmed by detection of hTGFα mRNA by northern RNA blot analysis, and the secreted hTGFα was measured by ELISA of culture supernatants. Tumor cells expressing hTGFα produced benign tumors (papillomas), which were 1.5- to 2-fold larger than tumors of parental cells when tested as skin grafts on nude mice. Grafts of normal cells that expressed hTGFα produced normal skin. When mixtures of parental tumor cells and normal mouse keratinocytes were grafted to nude mice, papilloma formation was suppressed and tumors that did form were small. Grafts of hTGFα-producing papilloma cells combined with either normal epidermal cells or hTGFα-producing epidermal cells yielded large tumors. Mixed grafts containing keratinocytes expressing hTGFα and parental papilloma cells also produced large tumors. While the tumor size was substantially increased by hTGFα expression, the tumors that developed in all groups were histologically benign and reached a stable size 4–5 wk after grafting. These results indicate that expression of hTGFα by either tumor cells (autocrine) or adjoining normal cells (paracrine) can stimulate tumor growth, particularly when tumor growth is suppressed by normal tissue. However, expression of this growth factor did not appear to influence tumor progression directly.