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Binding of Insulin-like Growth Factors to Tera-2 Human Embryonal Carcinoma Cells during Differentiation¹

Department of Medicine, Indiana University School of Medicine, and Richard L. Roudebush VA Medical Center and the Walther Oncology Center, Indianapolis 46202 [J. F. F., S. V. B., B. J. R., G. W. S.], and Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285 [K. S. H., C. A. F.]

Differentiation of Tera-2 human embryonal carcinoma cells by exposure to 2.1 mM -difluoromethylornithine resulted in changes in morphology, a decrease in growth rate, and changes in the expression of SSEA-1 differentiation antigen. While the binding of ¹²⁵I-insulin-like growth factor I (IGF-I) remained relatively constant during differentiation, binding of ¹²⁵I-IGF-II increased 2-3-fold. Further, the binding of IGF-II was 87 times greater than IGF-I in both undifferentiated and differentiated cells. Undifferentiated Tera-2 cells exhibited a single class of binding sites for both IGF-I (K_D = 1.2 nM, 7.0 x 10³ sites/cell) and IGF-II (K_D = 8.3 nM, 3.4 x 10⁵ sites/cell). Following differentiation, IGF-I continued to bind to a single class of binding sites (K_D 1.0 nM, 6.7 x 10³ sites/cell) whereas IGF-II bound to both high-affinity sites (K_DH 0.3 nM, 2.2 x 10⁵ sites/cell) and low-affinity sites (K_DL 15.1 nM, 1.6 x 10⁷ sites/cell). The binding of iodinated IGF-II was blocked by unlabeled IGF-II but not IGF-I. In contrast, ¹²⁵I-IGF-I binding was prevented by either IGF-I or IGF-II. Affinity cross-linking experiments demonstrated the presence of both type I and type II IGF receptors along with a number of IGF binding proteins. IGF-I failed to stimulate the incorporation of [³H]thymidine in both undifferentiated and differentiated cells. Although IGF-II caused a significant increase in [³H]thymidine incorporation in both undifferentiated and differentiated Tera-2 cells, the magnitude of the response and the sensitivity of the cells to IGF-II stimulation was diminished following differentiation. The observed changes in IGF-II binding, which occur in conjunction with cellular differentiation, may be an important feature of the expression of the differentiated phenotype by human germ cell tumors.

¹ J. F. F. is supported by Grant 203422/86-CL of the National Research Council of Brazil (CNPq). G. W. S. and B. J. R. are supported by a VA Merit Review Award and a grant from the Walther Cancer Foundation.

² To whom requests for reprints should be addressed, at Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285.

Received 5/ 7/90. Accepted 6/10/91.