He Yi-feng, Zhang Mei-ying, Wu Xin, Sun Xiang-jun, Xu Ting, He Qi-zhi, Di Wen
Shanghai Key Laboratory of Gynecologic Oncology, Department of Obstetrics and Gynecology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
PLoS One. 2013 Dec 6;8(12):e79769. doi: 10.1371/journal.pone.0079769. eCollection 2013.
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.
黏蛋白2（MUC2）是一种由卵巢癌细胞异常表达的黏蛋白分子。以往的体外研究表明，MUC2通过肿瘤相关巨噬细胞（TAM）依赖机制促进癌症生长和转移。然而，这一机制从未与临床肿瘤学联系起来，其预后意义有待阐明。在此，我们收集了102例连续的卵巢癌标本，并使用多重免疫组织化学/荧光技术来确定MUC2表达状态、M1/M2 TAM比例以及环氧合酶-2（COX-2）阳性TAM和COX-2阳性癌细胞密度之间的相关性。采用Kaplan-Meier生存分析和多因素Cox回归分析来评估这些参数的预后影响。结果，我们发现MUC2过表达（免疫染色++/+++）与M1/M2 TAM比例降低（p<0.001）、COX-2阳性TAM密度增加（p<0.001）以及COX-2阳性癌细胞密度增加（p=0.017）显著相关。此外，大多数M2 TAM（93%-100%）和COX-2阳性TAM（63%-89%）重叠；并且在COX-2阳性TAM附近经常观察到COX-2阳性癌细胞。在Cox回归分析中，发现MUC2过表达是卵巢癌患者的独立预后因素，其风险比（HR）为2.354（95%置信区间（CI）：？？？，p=0.005）。此外，M1/M2 TAM比例降低以及COX-2阳性TAM和COX-2阳性癌细胞密度增加被证明是预后不良的预测指标，其中M1/M2比例降低的HR最高（1.767，95%CI：1.061-6.957，p=0.019）。所有这些发现表明，MUC2可同时对TAM发挥M2极化和COX-2诱导作用，由此导致TAM M1/M2极化模式失衡并诱导局部前列腺素E₂合成（在TAM和癌细胞中均如此）。局部前列腺素E₂合成与TAM M2极化之间的正反馈加速了卵巢癌进展。 （原文中95%置信区间部分数据缺失，已标注问号）
