The Parity-Associated Microenvironmental Niche in the Omental Fat Band Is Refractory to Ovarian Cancer Metastasis
The Parity-Associated Microenvironmental Niche in the Omental Fat Band Is Refractory to Ovarian Cancer Metastasis
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DOI：
10.1158/1940-6207.capr-13-0227
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发表时间：
2013-11-01
影响因子：
3.3
通讯作者：
Roberts, Paul C.
中科院分区：
文献类型：
--
作者：
Cohen, Courtney A.;Shea, Amanda A.;Roberts, Paul C.
卵巢癌是老年女性的一种隐匿性、侵袭性疾病，由于其无症状且缺乏早期检测工具，通常在腹膜转移之前未被发现。流行病学研究表明，生育（产次）与卵巢癌风险降低有关，尽管造成这种现象的分子机制尚未阐明。卵巢癌优先转移至网膜脂肪带 (OFB)，这是一种辅助淋巴器官，有助于过滤腹膜浆液 (PSF) 并帮助对抗腹膜感染。在本研究中，我们评估了胎次和年龄如何影响小鼠 OFB 的免疫成分谱，无论是在稳态状态还是卵巢癌腹膜植入的结果。使用荧光激活细胞分选分析和定量实时 PCR，我们发现胎次与网膜单核细胞亚群和 B1-B 淋巴细胞的显着减少有关，与关键趋化因子和极化因子（Ccl1、Ccl2、Arg1 和 Cxcl13）的稳态表达水平降低相关。值得注意的是，与未产过的动物相比，经产的动物在腹膜内植入后表现出显着降低的肿瘤负荷。这与肿瘤相关的中性粒细胞和巨噬细胞及其趋化因子（Cxcl1 和 Cxcl5）在 OFB 和 PSF 中表达水平的减少有关。这些发现定义了OFB中预先存在的“与产次相关的微环境生态位”，该生态位难以抵抗转移性肿瘤的播种和生长。旨在操纵这一生态位的未来研究可能会提供一种减轻卵巢癌腹膜播散的新方法。
Ovarian cancer is an insidious and aggressive disease of older women, typically undiscovered before peritoneal metastasis due to its asymptomatic nature and lack of early detection tools. Epidemiologic studies suggest that child-bearing (parity) is associated with decreased ovarian cancer risk, although the molecular mechanisms responsible for this phenomenon have not been delineated. Ovarian cancer preferentially metastasizes to the omental fat band (OFB), a secondary lymphoid organ that aids in filtration of the peritoneal serous fluid (PSF) and helps combat peritoneal infections. In the present study, we assessed how parity and age impact the immune compositional profile in the OFB of mice, both in the homeostatic state and as a consequence of peritoneal implantation of ovarian cancer. Using fluorescence-activated cell sorting analysis and quantitative real-time PCR, we found that parity was associated with a significant reduction in omental monocytic subsets and B1-B lymphocytes, correlating with reduced homeostatic expression levels of key chemoattractants and polarization factors (Ccl1, Ccl2, Arg1, and Cxcl13). Of note, parous animals exhibited significantly reduced tumor burden following intraperitoneal implantation compared with nulliparous animals. This was associated with a reduction in tumor-associated neutrophils and macrophages, as well as in the expression levels of their chemoattractants (Cxcl1 and Cxcl5) in the OFB and PSF. These findings define a preexisting "parity-associated microenvironmental niche" in the OFB that is refractory to metastatic tumor seeding and outgrowth. Future studies designed to manipulate this niche may provide a novel means to mitigate peritoneal dissemination of ovarian cancer.