Analysis of Insulin-Like Growth Factor I Gene Expression in Malignancy: Evidence for a Paracrine Role in Human Breast Cancer

Abstract

Insulin-like growth factor I (IGF-I) activity has been reported to be produced by several human cancers. Identification of RNAs transcribed from the IGF-I gene has been complicated by the detection of multiple hybridizing bands on Northern analysis. To determine if any of these RNAs are transcribed from the IGF-I gene, we have used a sensitive and specific ribonuclease (RNAse) protection assay for IGF-I. We have also studied the breast cancer tissue expression of IGF-I using in situ hybridization histochemistry. We have found no IGF-I mRNA in breast (zero of 11) or colon cancer (zero of 9) cell lines; both of these tumors have been previously reported to express IGF-I mRNA. However, three of three neuroepithelioma and one of two Ewing's sarcoma cell lines express IGF-I mRNA; therefore, in these tumors IGF-I may be an autocrine growth factor. In contrast to breast cancer cell lines, RNA extracted from breast tissues has easily detectable IGF-I mRNA. In situ hybridizations show that IGF-I mRNA is expressed in the stromal cells, and not by normal or malignant epithelial cells. These findings suggest that although IGF-I is not produced by breast epithelial cells it may function as either a paracrine stimulator of epithelial cells or an autocrine stimulator of stromal cells.

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.…”

17β-Oestradiol treatment modulates nitric oxide synthase activity in MDA231 tumour with implications on growth and radiation response

“…An influence of stromal fibroblasts on the growth of breast carcinoma cells has been demonstrated in vivo (Gleiber and Schiffman, 1984). It has also been proposed that insulin-like growth factors that act synergistically with E 2 on breast cells, may also be produced by stromal cells (Yee et al, 1989;van der Burg et al, 1990). Depending on its concentration, the biological redox milieu and the involvement or induction of intracellular defence mechanisms, NO can either suppress apoptosis and eventually stimulate proliferation or activate the cell death programme (Lopez-Farre et al, 1998).…”

The GH–IGF-I axis and breast cancer

“…In situ hybridizations show that IGF-1 mRNA is expressed in the stromal cells and not by normal or malignant epithelial cells 32 . Cullen et al also showed that IGF-1 mRNA was commonly expressed in fibroblasts derived from non malignant biopsy specimens 33 .…”