Autocrine transforming growth factor-α is associated with progression of transformed properties in human colon cancer cells

The GEO colon carcinoma cell line is weakly tumorigenic in athymic mice and shows differentiated properties both in tissue culture and in xenografts. Proliferating monolayer cultures of GEO cells which normally require exogenous epidermal growth factor (EGF) for optimal growth displayed a marked inhibition in growth upon addition of antibodies that block binding to the EGF receptor or neutralize TGF-α. These results indicated that GEO cells utilize TGF-α in a weak autocrine loop. The availability of a weakly malignant model system in which TGF-α had demonstrable, but low level autocrine activity, permitted the investigation of the role of TGF-α in tumorigenesis by generating a stronger autocrine loop through the overexpression of the polypeptide. GEO cells were electroporated with an expression vector containing the human TGF-α cDNA, and stable clones were isolated that constitutively expressed the TGF-α cDNA in a strong autocrine loop. However, the growth rate of the parental cells in EGF-supplemented medium was the same as that of transfected cells with or without growth factor-supplemented medium. Thus, any biological changes generated by the overexpression of TGF-α were due to the autocrine nature of the growth mechanism rather than due to any decrease in doubling time leading to a faster growth rate. Transfected GEO cells showed an increase in anchorage-independent growth and formed tumors more readily in athymic nude mice indicating that TGF-α plays a role in progression of transformed properties.