Elevated Serum Insulin-Like Growth Factor-Binding Protein 2 (IGFBP-2) and Decreased IGFBP-3 in Epithelial Ovarian Cancer: Correlation with Cancer Antigen 125 and Tumor-Associated Trypsin Inhibitor1

Abstract

Insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) recently have been shown to play a physiological role in the female genital system, including the ovarian follicular system. However, little is known about the role of the IGF system in malignant ovarian disease. To assess possible mutual correlations between alterations in circulating IGFBP profiles and tumuor markers in patients with epithelial ovarian cancer, we performed an RIA for IGFBP-2 and IGFBP-3 and a Western ligand blotting (WLB) in serum samples from 20 patients with epithelial ovarian cancer, 10 patients with benign ovarian tumors, and 8 healthy age-matched controls. The epithelial ovarian cancer group had a mean IGFBP-2 level that was 253% (RIA) and 105% (WLB) above that of controls. IGFBP-2 even correlated positively with the highly sensitive serum tumor marker, cancer antigen 125 (CA 125) (r = 0.71, P < 0.001) but not with the less sensitive tumor-associated trypsin inhibitor. In contrast, serum IGFBP-3 (by RIA and WLB) was decreased in patients with ovarian cancer, and IGFBP-3 proteolytic activity was detectable in some of the patients. Neither IGFBP-3 nor IGFBP-3 proteolytic activity correlated with CA 125; but the former correlated inversely, and the latter positively, with tumor-associated trypsin inhibitor. In conclusion, IGFBP-2 levels are high in serum of epithelial ovarian cancer patients, and the increment in serum IGFBP-2 correlates positively with CA 125. Alterations in serum IGFBP-2 levels may therefore, serve as a potential additional marker for ovarian cancer.

Does IGF-1 play a role in the biology of ovarian cancer?

“…One might speculate that most of the 59 subjects were in fact postmenopausal at the time of blood collection, which would have significantly affected the final results. No significant correlations between the level of serum free IGF-1 in OC women and clinical and pathological parameters were found, which is consistent with all publications included in the study [10][11][12][25][26][27][28][29][30].…”

“…This hypothesis is therefore not an ideal explanation for the association between elevated serum IGF-1 levels and an increased risk for OC in young women. Lower serum IGF-1 levels in OC patients as compared to women with benign tumors and/or non-tumor women have also been reported by some authors [25][26][27][28][29]. Other researchers did not observe any statistically significant differences in serum IGF-1 levels in OC women as compared to non-cancer patients, and did not report any higher serum IGF-1-dependent risk for the development of OC [12,30].…”

“…It cannot be ruled out that OC women were more likely to suffer from cardiovascular diseases. As a result, the reported lower serum IGF-1 levels in OC patients did not result de facto from this pathology but a comorbid cardiovascular disease [25,26,29]. Moreover, Flyvbjerg et al, did not include data on BMI, diabetes mellitus (DM), and hormone replacement therapy (HRT) in their publication [25], which questions the reliability of the results, given the fact that both, BMI and DM have a proven effect on serum IGF-1 level [33,34].…”

“…As a result, the reported lower serum IGF-1 levels in OC patients did not result de facto from this pathology but a comorbid cardiovascular disease [25,26,29]. Moreover, Flyvbjerg et al, did not include data on BMI, diabetes mellitus (DM), and hormone replacement therapy (HRT) in their publication [25], which questions the reliability of the results, given the fact that both, BMI and DM have a proven effect on serum IGF-1 level [33,34]. Numerous studies have also indicated that oral HRT leads to a significant decrease in serum IGF-1 levels, which is probably due to direct inhibition of the synthesis of this factor in the liver by oral estrogen [35].…”

An Interaction between Insulin-like Growth Factor-binding Protein 2 (IGFBP2) and Integrin α5 Is Essential for IGFBP2-induced Cell Mobility

“…The enhanced expression of IGFBP2 was recently found to be one of the most frequent alterations in GBM (8 -12) and in some advanced stage cancers of the prostate (24,25) and ovaries (26,27). The fact that IGFBP2 is overexpressed only in advanced stages of these tumors suggests that IGFBP2 affects functional pathways critical in determining the phenotypes of these cancers, such as increased cell proliferation and invasion.…”