Circulating IGF system and treatment outcome in epithelial ovarian cancer

Abstract

Aggressive epithelial ovarian cancers (EOCs) frequently progress and become fatal, even when cytoreduction surgery plus platinum-based chemotherapy are performed. Thus, the early detection of high-risk subgroups is important in order to provide opportunities for better treatment outcomes, using alternative therapeutic strategies. This study aimed to explore the expression of circulating IGF system components and their relationship with treatment outcome in EOC. We included 228 patients with a median follow-up time of 44 months at two tertiary centers. There were 68 cancer deaths and 108 cases of cancer progression in the cohort. Preoperative serum levels of total IGF1, IGF2, IGF-binding protein 2 (IGFBP2), and IGFBP3 were analyzed using an ELISA and were then converted into an IGF1:IGFBP3 molar ratio. The risks of mortality and progression were estimated using Cox regression models in univariate and multivariate analyses. Our results showed that high IGF1, IGF2, and IGFBP3 levels were significantly associated with an early cancer stage, non-serous histology, and optimal cytoreduction. High IGFBP2 levels were associated with an advanced stage and serous histology. Overall and progression-free survival durations were significantly better among patients with high IGF1 (PZ0.003 and PZ0.001), IGF2 (PZ0.003 and PZ0.02), or IGFBP3 levels (PZ0.02 and PZ0.008). In multivariate analysis, serum IGFBP2 levels were significantly associated with increased risk of mortality (hazard ratioZ1.84, 95% CI: 1.07-3.18, PZ0.03), indicating that IGFBP2 could be used as an early predictor of EOCrelated mortality. The combination of elevated IGFBP2 and reduced IGF1 levels at diagnosis could further facilitate the identification of a patient subgroup with the worst prognosis. Key Words" insulin-like growth factor " insulin-like growth factor-binding protein " epithelial ovarian cancer " response to chemotherapy " prognosis

LIN-28B/let-7a/IGF-II axis molecular subtypes are associated with epithelial ovarian cancer prognosis

“…The association of IGF-II overexpression and increased risk of human cancer including ovarian cancer, and poor cancer survival has been reported previously [16,17]. Animal models and in vitro experiments show that IGF-IR inhibition can increase the efficacy of chemotherapy and suppress tumor-cell growth [18], suggesting that the suppression of IGF-II/IGF-IR may benefit patients with malignancies.…”

IGF2 signaling and regulation in cancer

“…In contrast to local production of IGF2, high circulating serum IGF2 in epithelial ovarian cancer patients is associated with favorable outcome (21). This points to a discordance between serum IGF2 levels, likely reflecting hepatocyte secretion, and tumor tissue expression of IGF2.…”

“…At least three non-mature IGF2 forms have been described to have biological activity: besides the 1-156 residue pro-IGF2, also the two so-called big IGF2s (1-87 and 1-104) (20) (Figure 2). The different intermediate forms of IGF2 are present in detectable quantities in the serum of both healthy people and patients affected by malignancies (21). In gastrointestinal stromal tumors, 91% of a cohort of tumors showed the presence of IGF2 mRNA, while benign tissue was negative.…”

Circulating Insulin-Like Growth Factor-1 Level and Ovarian Cancer Risk

“…After reviewing titles and abstracts, most studies were excluded and only 10 papers were selected as potentially relevant studies, which were further assessed for eligibility by reading full-text [16-23, 30, 31]. Three studies were further excluded for caseonly studies [18,21,30], and two studies were excluded for containing overlapping data [19,20]. Finally, five studies were included into the meta-analysis [16,17,22,23,31].…”