The insulin-like growth factor 1 pathway is a potential therapeutic target for low-grade serous ovarian carcinoma

Abstract

Objective

To validate the overexpression of insulin-like growth factor 1 (IGF-1) and its receptor (IGF-1R) in low-grade serous ovarian carcinoma (SOC), and to investigate whether the IGF-1 pathway is a potential therapeutic target for low-grade SOC.

Methods

Gene expression profiling was performed on serous borderline ovarian tumors (SBOTs) and low-grade SOC, and overexpression of IGF-1 in low-grade SOC was validated by RT-PCR and immunohistochemistry. The effect of exogenous IGF-1 on cell proliferation was determined in cell lines by cell proliferation assays, cell migration assays, and Western blot. Signaling pathways downstream of IGF-1 and the effects of the AKT inhibitor MK-2206 were investigated by Western blot analysis and by generating IGF-1R short hairpin RNA stable knockdown cell lines. Low- and high-grade cell lines were treated with the dual IGF-1R- and insulin receptor-directed tyrosine kinase inhibitor OSI-906, and cellular proliferation was measured.

Results

mRNA analysis and immunostaining revealed significantly higher IGF-1 expression in low-grade SOCs than in SBOTs or high-grade SOCs. In response to exogenous treatment with IGF-1, low-grade cell lines exhibited more intense upregulation of phosphorylated AKT than did high-grade cell lines, an effect that was diminished with IGF-1R knockdown and MK-2206 treatment. Low-grade SOC cell lines were more sensitive to growth inhibition with OSI-906 than were high-grade cell lines.

Conclusions

IGF-1 is overexpressed in low-grade SOCs compared with SBOTs and high-grade SOCs. Additionally, low-grade SOC cell lines were more responsive to IGF-1 stimulation and IGF-1R inhibition than were high-grade lines. The IGF-1 pathway is therefore a potential therapeutic target in low-grade SOC.

Introduction

It is generally accepted that low-grade and high-grade serous ovarian carcinomas (SOCs) evolve via molecularly and genetically distinct pathways [1], [2], [3]. Whereas high-grade SOCs are thought to arise de novo, a majority of low-grade SOCs tend to originate from molecular precursors, more specifically, serous borderline ovarian tumors (SBOTs) [4], [5]. This notion is supported by the fact that SBOTs frequently recur as low-grade SOCs [6], [7]. Singer et al. [8] observed a gradual accumulation of genetic mutations in the progression from SBOTs to low-grade SOCs, whereas high-grade SOCs harbored several mutations even in early stages of tumorigenesis, developing rapidly from surface epithelium—suggesting a dualistic mechanism for the development of serous ovarian carcinomas. As a result of these and other similar observations, many institutions have adopted a binary grading system for ovarian carcinoma, which is highly reproducible [9], [10].

Clinically, high-grade and low-grade SOCs behave differently as well. Women with advanced-stage low-grade SOC have higher 5-year survival rates than women with high-grade SOC [11], [12], an observation that reflects the indolent nature of low-grade SOC. Even though low-grade carcinomas portend improved overall survival, they are relatively chemoresistant and more difficult to treat upon recurrence [13], [14], and most patients with low-grade SOC eventually succumb to the disease. Despite these histologic and clinical differences, patients with low-grade and high-grade SOC are currently treated with the same standard protocol of surgery followed by platinum- and taxane-based chemotherapy.

New therapeutic strategies and novel molecular targets are needed to improve the outcome of this patient cohort. Recently, interest has emerged in the insulin-like growth factor (IGF) pathway as a potential therapeutic target. Downstream effectors of the IGF pathway, including phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) and RAF/mitogen-activated protein (MAP) kinase, have well-established roles as mitogens in carcinogenesis [15], [16]. Several clinical trials are also under way exploring the efficacy of IGF-1 receptor (IGF-1R) inhibitors in various malignancies. OSI-906 (OSI Pharmaceuticals, Melville, NY) is one such inhibitor, which dually targets the tyrosine kinase domain of IGF-1R and the insulin receptor (IR).

By gene expression profiling, we found that IGF-1 is highly expressed in low-grade SOCs in comparison to SBOTs. We hypothesize that the IGF-1 pathway is required for the pathogenesis of low-grade SOCs and is a potential therapeutic target for low-grade SOC. In this study, we sought to validate the over-expression of IGF-1 in low-grade SOCs, and to demonstrate that the IGF-1 pathway is a potential therapeutic target for low-grade SOCs.