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Insulin-like Growth Factor I and Transforming Growth Factor as Autocrine Growth Factors in Human Pancreatic Cancer Cell Growth¹

Department of Internal Medicine, Institute of Clinical Endocrinology, Tokyo Women's Medical College, 8-1 Kawada-cho, and Research Institute for Growth Sciences, Shinjuku-ku, Tokyo, 162 Japan

The roles of insulin-like growth factor I (IGF-I) and transforming growth factor (TGF-) as autocrine factors in the proliferation of MIA-PaCa 2 cells (human pancreatic cancer cells, PC cells) were investigated. Furthermore, the mechanism(s) of inhibition of PC cell growth by a phorbol ester in relation to these two kinds of growth factor was also studied.

PC cells grew autonomously when Dulbecco's modified essential medium supplemented with 4% fetal calif serum was changed to serum-free medium (0.3% bovine serum albumin-Dulbecco's modified essential medium). In addition, serum-free conditioned medium from PC cells dialyzed against fresh Dulbecco's modified essential medium had a stimulatory action on the growth of the same kind of cells when compared with that induced by nonconditioned medium. These observations suggest that a factor(s) produced and released by PC cells stimulates their own growth. Analysis of conditioned medium from PC cells revealed the presence of immunoreactive (IR)-IGF-I and IR-TGF-. The molecular size of IR-IGF-I was similar to that of authentic IGF-I. On the other hand, IR-TGF- was present as multiple forms when analyzed using gel chromatography. Authentic IGF-I and TGF- added to culture medium stimulated PC cell growth by 1.45- and 1.5-fold above control value, respectively. A monoclonal antibody to IGF-I receptor was able to inhibit PC cell growth.

PC cell proliferation was markedly inhibited by 12-O-tetradecanoyl-13-acetate (>0.16 nM), whereas cell growth of human fibroblasts was stimulated by it. 12-O-Tetradecanoyl-phorbol-13-acetate also reduced the binding of ¹²⁵I-IGF-, but not ¹²⁵I-IGF-I, to PC cells. Decrease in TGF- binding was mainly due to the reduced affinity of receptors to the ligand.

These results suggest that IGF-I and TGF- are involved in PC cell proliferation as autocrine factors. Further, the inhibition of PC cell growth by phorbol ester could be, at least partly, due to the decreased binding of TGF- to the cells.

¹ The present work was supported by grants from the Ministry of Education, the Ministry of Health and Welfare, and the Foundation for Growth Science.

Received 6/13/89. Revised 9/26/89. Accepted 10/ 3/89.

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