Abstract 5031: Insulin-like growth factor-1 (IGF-1) is upregulated in low-grade serous ovarian carcinoma

Abstract

Abstract Introduction: Low-grade (LG) serous ovarian carcinomas are clinically and genetically distinct from high-grade serous ovarian carcinomas (HG), and emerging evidence supports that LG form a molecular continuum with serous borderline ovarian tumors (SBOT). Despite an improved survival, LG ovarian cancer is relatively chemoresistant, and difficult to treat when it recurs. We sought to identify and validate the upregulation of IGF-1 in low-grade serous ovarian carcinomas. Methods: Gene expression profiling was performed with Affymetrix U133 to identify genes over-expressed in LG tumors compared to SBOT. Over-expression of IGF-1 in 18 LG tumors was validated by quantitative real-time polymerase chain reaction (qRT-PCR) and compared to IGF-1 expression in 9 serous borderline ovarian tumors (SBOT) and 15 HG tumors. Immunohistochemistry (IHC) of IGF-1 was performed on SBOT, LG, and HG samples and graded according to staining intensity. A low-grade cell line (HOC-7) was used to generate IGF-1 receptor (IGF-1R) knockdown stable cell lines with shRNA. Similarly, an IGF-1 plasmid was transfected into HOC-7 cells with resultant IGF-1 over-expression. Cells were then treated with IGF-1 at a concentration of 100 ng/mL for 15 and 60 minutes with controls. Phospho-Akt, total Akt, IGF-1R, and β-actin expression was confirmed by Western Blot analysis. Cell migration assays were performed with an HOC-7 control and shRNA IGF-1R knockdown cell lines. Finally, expression of IGF-1R was performed on LG paraffin sections and graded according to staining intensity on 43 patients. Clinical data including survival status, overall survival, stage, and debulking status was gathered and Kaplan-Meier curves were generated according to staining intensity. Results: In the Affymetrix analysis, several genes were significantly differentially expressed in LG tumors, one of which was IGF-1. Based on qRT-PCR results, expression of IGF-1 was significantly higher in LG tumors than SBOT (p<0.0005) and HG carcinomas (p=0.033). LG tumors also exhibited more robust IGF-1 IHC staining than SBOT or HG specimens. Phospho-Akt expression increased with increasing time of exposure to IGF-1 and in the IGF-1 over-expressing cell line compared to controls; whereas phospho-Akt expression was decreased in the IGF-1R knockdown cell lines. Decreased cellular migration was noted in the IGF-1R knockdown compared to the control. In the IHC analysis, 92% of the 43 LG slides stained positive for IGF-1R expression; however, correlation between staining intensity and patient survival was not significant. Conclusions: IGF-1 is overexpressed in low-grade serous epithelial ovarian tumors, and activates the phospho-Akt pathway through the IGF-IR. Particularly in LG ovarian tumors, which are less sensitive to chemotherapy and difficult to cure upon recurrence, further clinical investigation into the utility of IGF-targeted therapy is warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5031. doi:10.1158/1538-7445.AM2011-5031