ATX/LPA轴协同肿瘤相关巨噬细胞（TAM）促进子宫内膜癌微血管浸润的机制初探

Invasion and metastasis of endometrial carcinoma are closely linked blood vessel invasion (BVI). Tumor-associated macrophage (TAM) can regulate tumor microvascular infiltration and metastasis, but the molecular mechanism is not clear. Autotaxin/lysophosphatidic acid (ATX/LPA) can promote chronic inflammation and tumor metastasis. Whether it promotes the early microvascular invasion of endometrial cancer cells synergy with TAM has not been reported. Our study found that TAM, ATX and LPA receptors are highly expressed in endometrial carcinoma, and ATX/LPA promotes the migration of endometrial cancer cells together with TAM. On this basis, this study intends to use many methods such as immunofluorescence and PDX model to launch research from three aspects: ① to analyze the synergistic effect of TAM, ATX/LPA and IL-6 in blood vessel invasion(BVI) of endometrial carcinoma; ② to understand the role of ATX/LPA recruitment of TAM to regulate the expression of VEGF, MMPs, IL-6 and promote endometrial cancer invasion; ③ to clarify the effect of blocking ATX/LPA targeting TAM to inhibit the tumor microenvironment imbalance and vascular metastasis of endometrial carcinoma in vivo. This study will reveal the key molecular links in the early stage of endometrial cancer, and provide a theoretical basis for finding TAMs targeted drugs to prevent from endometrial carcinoma vascular invasion.

子宫内膜癌侵袭转移与血管浸润（BVI)密切相关。肿瘤相关巨噬细胞（TAM）可调控肿瘤微血管浸润及转移，但分子机制不清。自分泌移动因子/溶血磷脂酸（ATX/LPA）能促进慢性炎症与肿瘤转移，其是否协同TAM促进子宫内膜癌细胞早期微血管浸润，尚未见报道。本课题组研究发现内膜癌TAM，ATX及LPA受体高表达，ATX/LPA协同TAM促进内膜癌细胞迁移。在此基础上，本课题拟采用免疫荧光及PDX模型等方法从以下三方面进行研究：①分析TAM、ATX/LPA 和IL-6等因子在内膜癌血管浸润（BVI）中的协同作用；②研究ATX/LPA招募TAM，共同调控IL-6、VEGF、MMPs等因子表达促进内膜癌侵袭的作用；③动物体内研究阻断ATX/LPA靶向TAM抑制肿瘤微环境失衡及内膜癌血管转移的效应。以揭示内膜癌早期微血管浸润发生的关键分子环节，为寻找TAMs靶向药物，预防子宫内膜癌血管微浸润提供理论依据。

子宫内膜癌伴淋巴脉管间隙浸润(lymph vascular space involvement，LVSI)、肌层浸润(myometrial invasion，MI)、淋巴结转移(lymph node metastasis，LNM)和组织学分级（Grade）为 G3，其术后的复发危险性明显升高。本课题组临床数据显示，700例子宫内膜癌患者的淋巴结转移率为8.0%（56/700）。 LVSI、MI、Grade、宫颈间质侵犯（Cervial stromal invasion）是淋巴结转移的独立危险因素。 本课题借助了Nanostring PanCancer IO 360基因表达panel，从整体和宏观上对子宫内膜癌脉管癌栓浸润和淋巴结转移过程中的肿瘤微环境进行表征。结果显示，肿瘤相关巨噬细胞（tumor-associated macrophages，TAMs）参与LVSI的形成。肿瘤相关巨噬细胞分泌因子CCL18、IL6、COMP、MMP9及VEGFB等在LVSI形成过程中呈现显著高表达。本项目进一步在组织、细胞和分子水平验证了肿瘤相关巨噬细胞相关标志物CD63、CD168及分泌因子CCL18因子在LVSI形成过程中的正性调控作用。