Abstract
Mucin 2 (MUC2) is a mucin molecule aberrantly expressed by ovarian cancer cells. Previous in vitro studies have indicated that MUC2 promotes cancer growth and metastasis through a tumor-associated macrophage (TAM)-dependent mechanism. However, this mechanism has never been linked to clinical oncology, and its prognostic significance needed to be clarified. Here, we collected 102 consecutive ovarian cancer specimens and used the multiple immuno-histo-chemical/-fluorescent technique to determine the correlations between the MUC2 expression status, the ratio of M1/M2 TAMs and the densities of cyclooxygenase-2 (COX-2)+ TAMs and COX-2+ cancer cells. The Kaplan-Meier survival analysis and multivariate Cox regression analysis were used to evaluate the prognostic influences of these parameters. As a result, we found that the MUC2 overexpression (immunostaining ++/+++) was significantly correlated with a reduced ratio of M1/M2 TAMs (p<0.001), an increased density of COX-2+ TAMs (p<0.001) and an increased density of COX-2+ cancer cells (p=0.017). Moreover, most of the M2 TAMs (93%-100%) and COX-2+ TAMs (63%-89%) overlapped; and the COX-2+ cancer cells were frequently observed near the COX-2+ TAMs. In the Cox regression analysis, MUC2 overexpression was found to be an independent prognostic factor for ovarian cancer patients, of which the hazard ratio (HR) was 2.354 (95% confidence interval (CI): 1.031-10.707, p=0.005). Also, the reduced ratio of M1/M2 TAMs and the increased densities of COX-2+ TAMs and COX-2+ cancer cells were demonstrated to be the predictors of poor prognosis, among which the reduced M1/M2 ratio possessed the highest HR (1.767, 95% CI: 1.061-6.957, p=0.019). All these findings revealed that MUC2 can concurrently exert M2-polarizing and COX-2-inducing effects on TAMs, by which it causes an imbalanced TAM M1-/M2-polarization pattern and induces local PGE2 synthesis (in both TAMs and cancer cells). The positive feedback between local PGE2 synthesis and TAM M2-polarization accelerates ovarian cancer progression.
Highlights
Epithelial ovarian cancer threatens the health of adult women and is a leading cause of cancer-related mortality in postmenopausal females [1]
To differentiate the overexpression status of Mucin 2 (MUC2) from its baseline expression, we performed a parallel immunohistochemical experiment on 33 benign ovarian tumor specimens
The results demonstrated “+” MUC2-immunostaining in 36.4% of the benign cases, and no benign tumor cases with higher immunostaining levels were detected. These results suggest that the baseline MUC2 expression in benign ovarian tumors corresponds to MUC2-/+ immunostaining, whereas MUC2++/+++ immunostaining is more specific to malignant tumors and represents a genuine overexpression status [23,24,25]
Summary
Epithelial ovarian cancer threatens the health of adult women and is a leading cause of cancer-related mortality in postmenopausal females [1]. A series of mucin molecules (MUCs) aberrantly secreted by ovarian cancer cells were identified, including MUC1, MUC2 and MUC16 [4,5,6]. In vitro experiments performed by Inaba et al showed that MUC2 induced macrophages within cancer tissues to express cyclooxygenase-2 (COX-2) and release prostaglandin E2 (PGE2). These authors suggested that the macrophage-secreted PGE2 could in turn promote tumor growth and metastasis [12]. Their findings indicated that MUC2 may be used as an immune suppressor by cancer cells
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