IGF-I in epithelial ovarian cancer and its role in disease progression

Abstract

Insulin-like growth factor-I (IGF-I) is known to be involved in the development and progression of several types of solid tumors including ovarian cancer. IGF-I levels in local tissue is subject to both endocrine and paracrine/autocrine regulation. To investigate which regulation is more importantly involved in IGF-I action in ovarian cancer regarding tumor progression, we analyzed IGF-I mRNA expression (assuming only from paracrine/autocrine regulation) and peptide concentration (subject to both endocrine and paracrine/autocrine regulation) as well as a genetic polymorphism (CA dinucleotide repeats) in 215 epithelial ovarian cancer patients. Genomic DNA, total RNA and cytosol proteins were extracted from fresh tumor samples. Two alternatively spliced IGF-I transcripts (IGF-IA and IGF-IB) were analyzed using real-time PCR. Cytosol levels of free and total IGF-I were measured with enzyme-linked immunosorbent assay. DNA sizing analysis was performed to determine the CA polymorphism. The study showed that the CA polymorphism had a weak influence on IGF-I expression, but no effect on tumor progression. High levels of free, not total, IGF-I peptide were associated with elevated risk of disease progression (HR = 2.06; 95%CI: 1.22-3.50), and the association was independent of clinicopathologic features of the disease. One of the IGF-I transcripts (IGF-IA) had a similar but less significant impact on disease progression. Women with high IGF-I mRNA and peptide were at greater risk for disease progression compared to those with low in both (HR = 2.13; 95%CI: 1.13-3.95). These findings support the notion that IGF-I is involved in ovarian cancer progression and free IGF-I plays a more important role in the disease. The study also suggests that both endocrine and paracrine/autocrine are involved in the regulation of IGF-I activity in ovarian cancer.

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

“…In addition, not all factors which influence the regulation of serum IGF-1 have been fully elucidated. However, based on our results and the available literature, it seems safe to conclude that the level of IGF-1 in OC tissues is probably affected by endocrine and autocrine regulation, which is consistent with the results obtained by Brokow and Conover [6,38]. Studies conducted to clarify the role of IGF-1 (both, locally synthesized and peripherally circulating serum) in the biology of breast cancer, have confirmed the role of this factor in the oncogenesis of this tumor [35].…”

“…Both, in vitro and in vivo studies indicate that the local IGF-1 system is involved in the induction of tumor cell proliferation, invasion and neoangiogenesis [2][3][4][5]. Various sources have reported IGF-1 overexpression in both, tumor tissues of OC and tumor-derived fluid [6][7][8][9]. Researchers, inspired by the results of OC cell and tissue tests, started to investigate serum IGF-1 in women with OC.…”

Circulating IGF system and treatment outcome in epithelial ovarian cancer

“…Preclinical findings implicated IGF1 in the induction of cell proliferation and invasion (Cao et al 2007, Lau & Leung 2012. Furthermore, the positive effect of IGF1 on ovarian cancer progression was supported by the correlation of increased IGF1 expression in cancer tissues with disease progression (Brokaw et al 2007) or poor prognosis (Spentzos et al 2007). Similarly, IGF2 gene expression was found to be increased in tumors with poor prognosis (Sayer et al 2005, Lu et al 2006 and to be an independent predictor of poor survival (Sayer et al 2005).…”

P-cadherin cooperates with insulin-like growth factor-1 receptor to promote metastatic signaling of gonadotropin-releasing hormone in ovarian cancer via p120 catenin

“…To test this, we examined a set of inhibitors at effective concentrations that specifically inhibit various RTKs, including general RTKs (genistein), IGF-1R (AG1024), fibroblast growth factor receptor 1 (SU5402), epidermal growth factor receptor (EGFR) (AG1478) and hepatocyte growth factor receptor c-Met (K252a), which have been previously implicated in the progression and metastasis of ovarian cancer (Ellerbroek et al, 2001;Steele et al, 2001;Brokaw et al, 2007;Sawada et al, 2007). Among these inhibitors, we found that only genistein used to block RTK or AG1024 used to inhibit IGF-1R led to a marked decrease in p120 ctn activation ( Figure 3a) and translocation ( Figure 3b) following GnRHa stimulation.…”