A cDNA clone of human transforming growth factor alpha (TGF-alpha) was introduced into two different retroviral vectors under the transcriptional control of either the viral LTR, vector 1520, or an internal mouse metallothionein-1 promoter, vector 1522. Infection of normal rat kidney fibroblasts (NRK-49F) and mouse mammary epithelial cells (NOG-8), followed by selection, allowed isolation of individual colonies expressing human TGF-alpha. NRK-49F and NOG-8 1520 infectants conditioned their media with equivalent amounts of TGF-alpha protein but responded differently to autocrine stimulation. NOG-8 infectants formed colonies in soft agar and tumors in nude mice. However, while the NRK-49F infectants proliferated in the presence of transforming growth factor beta (TGF-beta), a response that requires epidermal growth factor (EGF) or TGF-alpha, they exhibited neither anchorage independent growth nor tumorigenicity. NRK-49F cells infected with the 1522 vector produced five-fold more TGF-alpha than the 1520 infectants. Increasing the level of TGF-alpha production by the NRK-49F cells in this way was sufficient to promote agar growth of the cells in the presence of TGF-beta but insufficient to promote tumorigenesis. The EGF receptor level is approximately ten-fold higher on the NOG-8 epithelial cells than on the NRK-49F fibroblast. This fact, in conjunction with the experimental results, suggest that the target cell type and its ability to respond to TGF-alpha is as critical for autocrine stimulation as the amount of growth factor produced by the cells.
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