Escapefromtransforming growthfactor f3control andoncogene cooperation inskintumordevelopment

Control oftumordevelopment bysurround- ingnormal cells hasbeensuggested byanumberofinvitro studies. Invivo, tumorigenicity ofras-transformed primary keratinocytes canbesuppressed byaddition ofnormal dermal fibroblasts. Here, wereport that dermal fibroblasts produce a diffusible inhibitory factor belonging tothetransforming growth factor P(TGF-P) family andpossibly corresponding to TGF-P3. Thisfactor cansuppress growth ofras-transformed primary keratinocytes inculture andafter injection into mice. Aswithprimary cells, tumorigenicity ofaras-transformed, TGF-,8-sensitive keratinocyte line issubstantially inhibited by adding dermal fibroblasts, leading totheformation ofmuch smaller anddifferentiated tumors. Introduction ofanintact Elaoncogene into these cells induces concomitant resistance to TGF-fl, totheeffect ofdermal-fibroblast inhibitory factor, and todermal-fibroblast tumorsuppression. Similar results are obtained withatransformation-deficient