阻断肿瘤微环境中TGF-β增强三阴乳腺癌脑转移瘤放疗敏感性及其机制研究

三阴乳腺癌脑转移常因放疗抵抗而进展。我们前期发现阻断原位乳腺癌微环境中TGF-β抑制血管生成，诱导肿瘤血管正常化而增强化疗药物的运输。预实验显示阻断三阴乳腺癌脑转移瘤微环境中TGF-β抑制肿瘤生长、血管生成和减少肿瘤间质细胞浸润；并且阻断细胞培养液中TGF-β能下调血管内皮细胞的miR-10a。据此提出假设：阻断三阴乳腺癌脑转移瘤微环境中TGF-β能通过抑制血管生成和调控间质细胞浸润而抑制肿瘤生长，且能诱导肿瘤血管正常化以改善组织缺氧增强肿瘤对放疗的敏感性，其诱导血管正常化的机制可能是调控内皮细胞特异microRNAs和下游靶基因的表达及其功能以诱导血管旁细胞向内皮聚集。我们拟应用裸鼠三阴乳腺癌脑转移模型及血管三维成像、缺氧标记物实验和一系列分子生物学方法，从体内、体外两方面证明上述假设，从而为治疗三阴乳腺癌脑转移提供新的靶点，为TGF-β抑制剂与放疗联用治疗三阴乳腺癌脑转移提供理论依据。

Brain metastatic triple negative breast cancer frequently progressed due to radiation resistance. Our previous study identified that blocking stromal TGF-β in orthotopic breast carcinoma could inhibit angiogenesis, and improve drug delivery via tumor vascular normalization. Preliminary results showed that blocking tumor microenvironmental TGF-β in the brain metastatic tumor of triple-negative breast cancer inhibited angiogenesis, decreased the infiltration of tumor associated stromal cells, and suppressed tumor growth; and TGF- β blockade could significantly down-regulate the miR-10a expression of vascular endothelial cells in vitro. Therefore, we hypothesize that blocking tumor microenvironmental TGF-β in brain metastatic tumor of triple-negative breast cancer could suppress tumor growth via inhibition of angiogenesis and regulation of stromal cells infiltration, and increase the radiosensitivity of brain metastatic tumor by inducing tumor vascular normalization and consequently improving tumor hypoxia. The mechanism of TGF-β blockade-induced vascular normalization might be due to inducement of pericyte recruitment to vascular endothelium by regulation of the expressions and functions of specific microRNAs and their target genes in endothelial cells. We plan to use brain metastatic triple-negative breast cancer nude mice xenografts, vascular imaging, pimonidazole experiment, and in vitro. molecular biology methods to prove the hypothesis. Our study will help to find novel therapy target for triple negative breast cancer with brain metastasis, and may provide strong preclinical evidence for conducting clinical trials on combining anti-TGF-β antibodies and radiation therapy in treating triple-negative breast cancer patients with brain metastasis.