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Loss of Growth Factor Dependence and Conversion of Transforming Growth Factor-ß₁ Inhibition to Stimulation in Metastatic H-ras-transformed Murine Fibroblasts¹

Manitoba Institute of Cell Biology, and Departments of Biochemistry [L. C. S., J. A. W.] and Immunology [M. C. G., A. H. G.], The University of Manitoba, 100 Olivia Street, Winnipeg, Manitoba R3E OV9, Canada

Cell lines with varying tumorigenic and metastatic potentials have been obtained by transformation of 10T fibroblasts using radiation or transfection with T-24 H-ras. We have observed an inverse relationship between metastatic potential and dependence on serum for growth. The effects of basic fibroblast growth factor, platelet-derived growth factor, epidermal growth factor, and transforming growth factor-ß₁ (TGF-ß₁) on these lines were then examined to determine if the changes in the serum dependence of metastatic cells may be due to altered responsiveness to specific growth factors (GFs). Cells were grown in monolayer culture and DNA synthesis was measured by [CH₃-³H]thymidine incorporation experiments. Both metastatic and nonmetastatic cells were shown to be equivalent in their diminished responsiveness to basic fibroblast growth factor, platelet-derived growth factor, and epidermal growth factor as compared to their nontransformed, parental 10T cells. However, a unique response of metastatic cells to TGF-ß₁ was identified. While TGF-ß₁ inhibited DNA synthesis in 10T cells and a nonmetastatic tumor, cells with intermediate to high metastatic ability were stimulated up to 5.8-fold by TGF-ß₁. Interestingly, epidermal growth factor abrogated the TGF-ß₁ inhibition of the parental 10T cells, but had no effect on the TGF-ß₁ response of any metastatic line. Therefore, metastatic but not nonmetastatic cells, demonstrated a dramatically altered sensitivity to TGF-ß₁, a response which may be important in determining metastatic potential.

¹ Supported by the National Cancer Institute of Canada and the Medical Research Council of Canada.

² Recipient of a Postdoctoral Studentship from the Manitoba Health Research Council.

³ Terry Fox Cancer Research Scientist of the National Cancer Institute of Canada.

⁴ Senior Research Scientist of the National Cancer Institute of Canada. To whom requests for reprints should be addressed, at Manitoba Institute of Cell Biology, 100 Olivia Street, Winnipeg, Manitoba, Canada R3E OV9.

Received 3/ 3/88. Revised 7/21/88. Accepted 9/16/88.

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