Epithelial ovarian cancer is characterized by a low recovery rate because the disease is typically diagnosed at an advanced stage, by which time most patients (80%) already exhibit disseminated neoplasia. The cytokine receptor CXCR4 has been implicated in the development of metastasis in various tumor types. Using a patient-derived tissue macroarray and mRNA expression analysis, we observed high CXCR4 levels in high-grade serous epithelial ovarian carcinomas, the most metastatic tumor, compared with those in endometrioid carcinomas. CXCR4 inhibition by treatment with the CXCR4 antagonist AMD3100 or by expression of shRNA anti-CXCR4 similarly inhibited angiogenesis in several models of ovarian carcinomas orthotopically grown in nude mice, but the effect on tumor growth was correlated with the levels of CXCR4 expression. Moreover, CXCR4 inhibition completely blocked dissemination and metastasis. This effect was associated with reduced levels of active Src, active ERKs, the inhibition of EMT transition, and block of hematogenous ovarian cancer dissemination decreasing circulating human tumoral cells (CTC). In tumors, CXCR4-expressing cells also had more mesenchymal characteristics. In conclusion, our results indicate that CXCR4 expression confers a proinvasive phenotype to ovarian carcinoma cells. Thus, anti-CXCR4 therapy is a possible agent for a complementary treatment of advanced disseminated epithelial high-grade serous ovarian cancer patients. Mol Cancer Ther; 17(2); 532–43. ©2017 AACR.

中文翻译：

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CXCR4 在腹膜和血源性卵巢癌播散中的作用

上皮性卵巢癌的特点是恢复率低，因为该疾病通常在晚期被诊断出来，此时大多数患者 (80%) 已经表现出播散性肿瘤。细胞因子受体 CXCR4 与各种肿瘤类型的转移发展有关。使用源自患者的组织宏阵列和 mRNA 表达分析，我们观察到与子宫内膜样癌相比，高级别浆液性上皮性卵巢癌（转移性最强的肿瘤）中的 CXCR4 水平较高。在裸鼠原位生长的几种卵巢癌模型中，通过用 CXCR4 拮抗剂 AMD3100 处理或通过表达 shRNA 抗 CXCR4 抑制 CXCR4 类似地抑制血管生成，但对肿瘤生长的影响与 CXCR4 表达水平相关。而且，CXCR4 抑制完全阻止传播和转移。这种效应与活性 Src、活性 ERK 水平降低、EMT 转变抑制和血源性卵巢癌传播阻断减少循环人类肿瘤细胞 (CTC) 相关。在肿瘤中，表达 CXCR4 的细胞也具有更多的间充质特征。总之，我们的结果表明 CXCR4 表达赋予卵巢癌细胞侵袭性表型。因此，抗 CXCR4 疗法可能是晚期播散性上皮性高级别浆液性卵巢癌患者的补充治疗药物。摩尔癌症治疗; 17(2); 532-43。©2017 AACR。和阻断血源性卵巢癌传播减少循环人类肿瘤细胞 (CTC)。在肿瘤中，表达 CXCR4 的细胞也具有更多的间充质特征。总之，我们的结果表明 CXCR4 表达赋予卵巢癌细胞侵袭性表型。因此，抗 CXCR4 疗法可能是晚期播散性上皮性高级别浆液性卵巢癌患者的补充治疗药物。摩尔癌症治疗; 17(2); 532-43。©2017 AACR。和阻断血源性卵巢癌传播减少循环人类肿瘤细胞 (CTC)。在肿瘤中，表达 CXCR4 的细胞也具有更多的间充质特征。总之，我们的结果表明 CXCR4 表达赋予卵巢癌细胞侵袭性表型。因此，抗 CXCR4 疗法可能是晚期播散性上皮性高级别浆液性卵巢癌患者的补充治疗药物。摩尔癌症治疗; 17(2); 532-43。©2017 AACR。抗 CXCR4 疗法可能是晚期播散性上皮性高级别浆液性卵巢癌患者的补充治疗药物。摩尔癌症治疗; 17(2); 532-43。©2017 AACR。抗 CXCR4 疗法可能是晚期播散性上皮性高级别浆液性卵巢癌患者的补充治疗药物。摩尔癌症治疗; 17(2); 532-43。©2017 AACR。