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Autocrine Transforming Growth Factor Is Dispensible for v-ras^Ha-induced Epidermal Neoplasia: Potential Involvement of Alternate Epidermal Growth Factor Receptor Ligands¹

Laboratory of Cellular Carcinogenesis and Tumor Promotion, Division of Cancer Etiology, National Cancer Institute, Bethesda, Maryland 20892 [A. A. D., C. C., E. K. W., N. D., S. H. Y.]; Departments of Medicine and Cell Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 [P. J. D., R. J. C.]; and Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Victoria 3050, Australia [B. M., A. R. D.]

Autocrine epidermal growth factor receptor activation by transforming growth factor (TGF) has been implicated in growth stimulation during epithelial neoplasia. Using keratinocytes isolated from mice with genetic defects in TGF expression, we tested whether TGF is required for transformation by the v-ras^Ha oncogene. Introduction of v-ras^Ha into primary epidermal cultures using a retroviral vector stimulated growth of both control (TGF +/+, BALB/c) and TGF-deficient (TGF -/-, wa-1) keratinocytes. Moreover, v-ras^Ha elicited characteristic changes in marker expression (keratin 1 was suppressed; keratin 8 was induced), previously shown to be associated with epidermal growth factor (EGF) receptor activation, in both TGF +/+ and TGF -/- keratinocytes. v-ras^Ha markedly increased secreted (>10-fold) and cell-associated (2–3-fold) TGF levels in keratinocytes from TGF +/+ and BALB/c mice, but not TGF -/- or wa-1 mice. Based on Northern blot analysis, v-ras^Ha induced striking up-regulation of transcripts encoding the additional EGF family members amphiregulin, heparin-binding EGF-like growth factor, and betacellulin in cultured keratinocytes from all four mouse strains. Interestingly, in addition to the normal 4.5-kilobase TGF transcript, wa-1 keratinocytes expressed two additional TGF transcripts, 4.7 and 5.2 kilobases long. All three transcripts were up-regulated in response to v-ras^Ha, as well as exogenous TGF or keratinocyte growth factor treatment, and were also detected in RNA isolated from wa-1 brain and skin. In vivo, v-ras^Ha keratinocytes from control as well as TGF-deficient mice produced squamous tumors when grafted onto nude mice, and these lesions expressed high levels of amphiregulin, heparin-binding EGF-like growth factor, and betacellulin mRNA, regardless of their TGF status. These findings indicate that TGF is not essential for epidermal neoplasia induced by the v-ras^Ha oncogene and suggest that another EGF family member(s) may contribute to autocrine growth stimulation of ras-transformed keratinocytes.

¹ This work was supported in part by a Thomas B. Fitzpatrick-Kao Corporation Research Award (A. A. D.), and by Grant MCICA46413 and by the Veterans Administration (R. J. C.). R. J. C. is a Veterans Administration Clinical Investigator.

² To whom requests for reprints should be addressed, at LCCTP/NCI, Bldg 37/Rm 3B08, 37 Convent DR MSC 4255, Bethesda, MD 20892-4255.

Received 12/ 1/94. Accepted 2/24/95.

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