IGF axis gene expression patterns are prognostic of survival in epithelial ovarian cancer

Abstract

The IGF axis has documented growth-promoting effects in various malignancies, but its role in epithelial ovarian cancer (EOC) has not been adequately examined. We studied the expression of the IGF axis genes in relation to outcome in EOC. Microarray expression profiles from 64 patients with advanced-stage EOC were used. Two multi-gene subsets were chosen, one upstream of the IGF receptor ('IGF family') and the other downstream of the IGF receptor ('IGF signaling pathway'), and analyzed in relation to survival. In addition, expression patterns of the two gene subsets were analyzed in relation to favorable and unfavorable prognosis categories identified in a previous study by whole-genome expression profiling. In a gene-by-gene analysis, IGF binding protein 4 and IGF-II receptor gene expression was inversely associated with survival. Using hierarchical clustering, the two multi-gene subsets separated the patient cohort into two groups with different median survival (IGF family: 33 vs 63 months, PZ0.02 and IGF signaling pathway: 41 vs 63 months, PZ0.05). Furthermore, the two multi-gene subsets were differentially expressed between the previously defined favorable and unfavorable prognosis tumors (Kolmogorov-Smirnov permutation: PZ0.0005 and 0.003 for the IGF family and signaling pathway respectively), and individual genes (including IGF-I, IGF-I receptor, and several genes downstream of the receptor) were overexpressed in unfavorable prognosis tumors (permutation P!0.05). The expression patterns of several genes in the IGF axis are associated with survival in EOC, and expression changes of these genes may be underlying previously proposed microarray-derived clinical prognostic models. Future studies are needed to more precisely determine the diagnostic and potential therapeutic significance of these findings.

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

“…This finding is also supported by our result in human ovarian cancer tissue, as per which a strong positive correlation between the expression of P-cadherin and phospho-IGF-1R was identified and was more predominant in the corresponding metastasis. The interaction between P-cadherin and IGF-1R is also especially interesting in view of the fact that IGF-1R is frequently overexpressed in ovarian cancer and confers a poor clinical prognosis (Spentzos et al, 2007). Similar associations between IGF-1R expression and adverse prognosis are also described in other cancer models, including breast, lung and colon cancer (Dunn et al, 1998;Takahari et al, 2009;Yim et al, 2009).…”

Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer

“…In this context, we have found that P-cadherin was able to transactivate the insulin-like growth factor-1 receptor in regulation of p120 ctn signaling (our unpublished observations). This is also relevant to the clinical situation as insulin-like growth factor-1 receptor is frequently overexpressed in ovarian cancer and confers adverse prognosis (Spentzos et al, 2007).…”