Insulin-Like Growth Factor-ll (IGF-II): A Potential Autocrine/Paracrine Growth Factor for Human Breast Cancer Acting via the IGF-I Receptor

Abstract

Insulin-like growth factor-II (IGF-II) is a potent mitogen for several types of cultured cells and tissues. We have studied the interaction of IGF-II with a panel of cultured human breast cancer cell lines, examining the possibility that these cells synthesize and secrete IGF-II activity which could have autocrine/paracrine functions. Synthetic IGF-II was mitogenic in five of seven cell lines tested, including the estrogen receptor-positive lines MCF-7L, ZR75-1, and T47D and the estrogen receptor (ER)-negative lines Hs578T and MDA-231. IGF-II was slightly less potent than IGF-I in stimulating DNA synthesis in MCF-71 cells, an effect that paralleled its ability to compete for [125I]IGF-I binding in these cells. Affinity labeling studies revealed that IGF-II could also compete for binding to the 130,000 mol wt alpha-subunit of the IGF-I receptor. A monoclonal antibody to the IGF-I receptor inhibited the mitogenic effects of IGF-II in MCF-7L and MDA-231 cells, suggesting that this receptor mediates the growth effects of IGF-II in these breast cancer cells. Using a RIA and a RRA, IGF-II-like activity was detected in conditioned medium extracts processed to remove IGF-binding proteins from several breast cancer cell lines, with the highest levels found in conditioned medium from MCF-7L and T47D cell lines. IGF-II mRNA transcripts in MCF-7L and T47D cells were identified by Northern blot analysis and were confirmed by RNase protection assay. IGF-II mRNA was increased by estrogen in MCF-7L cells.(ABSTRACT TRUNCATED AT 250 WORDS)

A recombinant humanized anti‐insulin‐like growth factor receptor type I antibody (h7C10) enhances the antitumor activity of vinorelbine and anti‐epidermal growth factor receptor therapy against human cancer xenografts

“…These results are in agreement with the observation of a straight correlation between estrogen and IGF-IR expression. 57 Estrogens induce the expression of several members of the IGF cascade including IGF-II, 58 IGF-IR 59 and IRS-1. 60 The increased expression of IGF-IR and IRS-1 results in an enhanced response to IGF-I, which in turn directly increases the transcriptional activity of the estrogen receptor.…”

Human breast carcinoma desmoplasia is PDGF initiated

“…Similarly stromal cells secrete both autocrine and paracrine factors. Looking at human tumor desmoplasia there are a number of autocrine and paracrine loops in play, some involving growth stimulation and some involving growth inhibition (Horgan et al, 1987;Adams et al, 1988;Osborne et al, 1989;Yee et al, 1989). PDGF, however, is the only factor out of the many growth factors secreted by breast carcinoma cells to have a sole paracrine action on neighboring stromal cells.…”

Expression of prostate-specific antigen (PSA) correlates with poor response to tamoxifen therapy in recurrent breast cancer

“…In analogy to uPA, the relationship of PSA to a poor response to tamoxifen therapy, which does not affect PSA expression in vitro (Zarghami et al, 1997), may, for example, be due to a local increase in the concentration of bioavailable IGFs by cleaving IGFBPs (Cohen et al, 1992(Cohen et al, , 1994Figueroa and Yee, 1992;Kanety et al, 1993) through tumour cell-secreted PSA. The free IGFs, abundantly present around the tumour cells because of the focal action of secreted PSA, are potent mitogens for breast cancer cells (Osborne et al, 1989;Cullen et al, 1990). They may disturb the balance and abolish the growth inhibitory effects induced by tamoxifen, despite a reduction in total serum levels of IGFs (Pollak et al, 1990;Lonning et al, 1992;Yee et al, 1994).…”

“…Insulin-like growth factor I and II (IGF-I and -II) are known as potent mitogens for breast cancer cells (Osborne et al, 1989;Cullen et al, 1990). Binding of IGFs to their binding proteins (IGFBPs) can reduce their mitogenic response (Figueroa and Yee, 1992).…”