IGFBP-2 EXPRESSION IN A HUMAN CELL-LINE IS ASSOCIATED WITH INCREASED IGFBP-3 PROTEOLYSIS, DECREASED IGFBP-1 EXPRESSION AND INCREASED TUMORIGENICITY

Insulin-like growth factors (IGF-I and -II) play an active role in cel l proliferation. In biological fluids, they are noncovalently bound to high-affinity binding proteins (IGFBPs), at least 6 species of which have been identified to date, but with poorly defined functions. One o f these IGFBPs, IGFBP-2, is secreted by most cell lines and appears to be involved in cell proliferation. A human epidermoid carcinoma cell line, KB 3.1, which produces IGFBP-1 and -3 and small amounts of IGFBP -4, but no IGFBP-2, was stably transfected with an expression vector c omprising IGFBP-2 complementary DNA (cDNA), whose expression was place d under the control of the constitutive and ubiquitous cytomegalovirus promoter. After an s.c. injection of these IGFBP-2-expressing KB 3.1 cells into nude mice, tumours developed more quickly than in controls, they were 3 to 4 times larger and grew about 3 times as fast. Concomi tant with IGFBP-2 expression in these tumours, were a decrease in IGFB P-1 expression and an increase in IGFBP-3 proteolysis, both of which i ncrease the bioavailability of the IGF-II produced by the cells. The i ncreased IGFBP-3 proteolysis most probably resulted from amplified exp ression of tissue-type plasminogen activator (GPA) and depression of i ts inhibitor (PAI-I) observed in IGFBP-2 expressing xenografts. Our fi ndings suggest that IGFBP-2 plays a role in this model of experimental tumorigenesis via a mechanism that remains unclear, but appears to in volve increased protease activity and IGF-II bioavailability. (C) 1998 Wiley-Liss, Inc.