Increased insulin-like growth factor binding protein-2 (IGFBP-2) gene expression and protein production lead to high IGFBP-2 content in malignant ovarian cyst fluid

Abstract

Summary Expression of insulin-like growth factor-I (IGF-I), its receptor and IGF-binding proteins (IGFBPs) by ovarian cancer cells and its mitogenic effect on these cells in vitro, suggest that IGF-I may have a role in regulation of human ovarian cancer. We have recently shown IGFBP-2 to be markedly elevated in malignant ovarian cyst fluid in vivo. To identify the origin of increased IGFBP-2 in these cyst fluids, the gene expression and protein content of IGFBP-2 were investigated in 14 malignant and four benign epithelial ovarian neoplasms. IGFBP-2 mRNA was detected in all ovarian specimens and was 2-to 30-fold higher in malignant than in benign neoplasms. Within the malignant tissues IGFBP-2 mRNA levels correlated with the aggressiveness of the tumour and were higher in invasive tumours than in those with borderline pathology. Southern blot analysis revealed no amplification of IGFBP-2 gene in the DNA samples from ovarian tumours regardless of their nature. IGFBP-2 was the major binding protein in tissue extracts, as measured by both Western ligand blotting and immunoblotting, and was significantly higher in malignant than in benign neoplasms. These findings were further supported by immunohistochemical detection of IGFBP-2 in tumour sections. Our data suggest that increased local production by the tumour in vivo is responsible for the increased IGFBP-2 levels in the cyst fluid bathing the ovarian malignancy. This may represent an autocrine regulatory mechanism for IGF-I proliferative effect of ovarian cancer.

Insulin-like growth factor-binding protein 2 and 5 are differentially regulated in ovarian cancer of different histologic types

“…These findings are consistent with a previous observation that increases in serum IGFBP2 are caused mainly by the markedly increased production of IGFBP2 by tumor cells in vivo. 10 In addition, some studies have shown that patients with malignant ovarian tumors have significantly higher serum levels of IGFBP2 compared with benign controls. 11,12 In contrast, only 18% of clear cell carcinomas and 37% of mucinous ovarian carcinomas showed moderate to strong staining for IGFBP2.…”

“…8,9 Among the IGFBPs expressed in ovarian cancers, IGFBP2 is markedly increased and significantly higher in cystic fluid from malignant epithelial ovarian tumors than in cystic fluid from benign epithelial ovarian tumors, mainly due to the increase in mRNA and protein expression in the tumor cells. 10 Serum IGFBP2 levels are also significantly higher in patients with ovarian cancer compared with benign controls. 11,12 Serum IGFBP2 levels in patients with ovarian cancers correlates positively with the ovarian tumor marker, CA-125.…”

Circulating IGF system and treatment outcome in epithelial ovarian cancer

“…Accumulating evidence supports the idea that IGFBP2 might act as a promoter, rather than a tumor suppressor, in EOC. This evidence includes the overexpression of both the IGFBP2 gene and protein in malignant ovarian cyst fluid (Kanety et al 1996), activated cell invasion in response to IGFBP2 induction (Lee et al 2005), and the concurrent elevation of IGFBP2 levels in EOC tumor tissues and serum (Lancaster et al 2006).…”

Insulin-like Growth Factors and Ovarian Cancer Risk: A Nested Case-Control Study in Three Cohorts

“…IGFBP-3 is the primary binding protein of IGF-I and levels seem to be lower in women with ovarian cancer versus benign lesions (5)(6)(7)(8). IGFBP-2 is commonly overexpressed by ovarian cancer cells (11)(12)(13), and retrospective studies report higher IGFBP-2 levels in cases versus controls (5,7,8). However, prospective studies have not observed an association between these binding proteins and ovarian cancer risk (3,4,14).…”