IGFBP-2 expression in a human cell line is associated with increased IGFBP-3 proteolysis, decreased IGFBP-1 expression and increased tumorigenicity

Abstract

Insulin‐like growth factors (IGF‐I and ‐II) play an active role in cell proliferation. In biological fluids, they are non‐covalently bound to high‐affinity binding proteins (IGFBPs), at least 6 species of which have been identified to date, but with poorly defined functions. One of 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 comprising IGFBP‐2 complementary DNA (cDNA), whose expression was placed 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. Concomitant with IGFBP‐2 expression in these tumours, were a decrease in IGFBP‐1 expression and an increase in IGFBP‐3 proteolysis, both of which increase the bioavailability of the IGF‐II produced by the cells. The increased IGFBP‐3 proteolysis most probably resulted from amplified expression of tissue‐type plasminogen activator (t‐PA) and depression of its inhibitor (PAI‐1) observed in IGFBP‐2‐expressing xenografts. Our findings suggest that IGFBP‐2 plays a role in this model of experimental tumorigenesis via a mechanism that remains unclear, but appears to involve increased protease activity and IGF‐II bioavailability. Int. J. Cancer 77:874‐879, 1998.© 1998 Wiley‐Liss, Inc.

Elevated serum insulin-like growth factor binding protein-2 is associated with a high relapse risk after hematopoietic stem cell transplantation in childhood AML

“…An increase of IGFBP-2 expression might be directly correlated to the increased cell proliferation rate. 31 Hettmer et al 32 recently published data demonstrating that incubation with exogenous IGFBP-2 increased the proliferation of PBMC; whereas, anti-IGFBP-2 had an antiproliferative effect on PBMC that was reversed by simultaneous exposure to IGFBP-2. These data strongly suggest a role for IGFBP-2 as a local growth factor contributing to the proliferation and activation of mononuclear cells.…”

Changes of serum growth factors (IGF-I,-II and IGFBP-2,-3) prior to and after stem cell transplantation in children with acute leukemia

“…An increase of IGFBP-2 expression might be directly correlated to the increased cell proliferation rates has been reported. 19 Human cell lines with IGFBP-2 expression showed higher tumorigenicity compared to cell lines without or lower IGFBP-2 expression. These data are confirmed by Mohnike et al, 20 who investigated children with leukemia at the time of diagnosis.…”

The IGF system in neuroblastoma xenografts: focus on IGF-binding protein-6

“…IGFBP-2 is frequently co-expressed with IGF-II, its expression is associated with cell proliferation and its serum concentrations rise in a variety of malignancies (Reeve et al 1992, Müller et al 1994, Flyvbjerg et al 1997, Fuller et al 1999. The mechanism by which IGFBP-2 is involved in cell proliferation may depend on the IGF system, as suggested by our earlier observation that in the presence of IGFBP-2, IGFBP-3 proteolysis is enhanced, thus increasing IGF bioavailability (Menouny et al 1998). It is also possible that IGFBP-2 possesses intrinsic activity that is independent of IGF binding, as evoked by Hoeflich et al (2000) in an adrenocortical cell model.…”