肿瘤相关巨噬细胞诱导肌成纤维细胞分化并促进乳腺叶状肿瘤恶性进展的机制研究

Phyllodes tumors (PT) of breast, even histologically diagnosed as benign, can recur locally and have metastatic potential. Histologic markers only have limited value in predicting the clinical behavior of PT. It remains unknown what drives the malignant progression of PT. Our previous study showed miR-21 induced fibroblast differentiation into myofibroblast and promoted the malignant progression of breast PT. Our preliminary experiments demonstrated that the expression level of CCL18, one of the specific molecular markers of tumor associated macrophages (TAMs), was statistically significantly higher in malignant tumors than that in the benign tumors. We further confirmed that TAMs could induce myofibroblast differentiation in PT. All these studies suggest that CCL18 may induce myofibroblast differentiation by regulating the expression of miR-21. In order to clarify the role of TAMs in the regulation of myofibroblast differentiation, we will further explore the molecular mechanism of CCL18 regulation of miR-21 and verify CCL18 promote malignant transformation of PT in vitro and in vivo. Finally, we will demonstarate the clinical significance of TAMs in PT progression. Our study will provide a new insight and new targets in inhibiting the recurrence and metastasis of breast PT.

乳腺叶状肿瘤易复发，且恶性叶状肿瘤具有较高的血行转移倾向。目前促进叶状肿瘤恶性转化的分子机制不明确，缺乏准确预测患者预后的组织学分子标记物。我们前期的研究发现：miR-21诱导叶状肿瘤细胞中成纤维细胞向肌成纤维细胞分化，促进了肿瘤的恶性转化；同时我们发现肿瘤相关巨噬细胞（TAMs）的特异性分子标记物CCL18在恶性叶状肿瘤中高表达，且我们已经证实TAMs可促进肌成纤维细胞分化，提示CCL18可能通过调控miR-21诱导肌成纤维细胞的分化。在此基础上，我们拟进一步探索TAMs通过CCL18调控miR-21的分子机制，在体内外模型中验证CCL18通过调控miR-21,诱导肌成纤维细胞的分化，进而促进叶状肿瘤恶性转化的功能，揭示TAMs在叶状肿瘤恶性进展过程中的作用和临床意义，本课题的完成将为遏制叶状肿瘤复发和转移提供新的思路和新的靶点。

乳腺叶状肿瘤易复发，且恶性叶状肿瘤具有较高的血行转移倾向。目前促进叶状肿瘤恶性转化的分子机制不明确，缺乏准确预测患者预后的组织学分子标记物。我们前期的研究发现：miR-21诱导叶状肿瘤细胞中成纤维细胞向肌成纤维细胞分化，促进了肿瘤的恶性转化；同时我们发现肿瘤相关巨噬细胞（TAMs）的分子标记物CCL18在恶性叶状肿瘤中高表达，且我们已经证实TAMs可促进肌成纤维细胞分化，提示CCL18可能通过调控miR-21诱导肌成纤维细胞的分化。在此基础上，我们进一步探索了CCL18调控miR-21的分子机制，在体内外模型中验证CCL18通过激活NF-kB,上调miR-21,进而诱导肌成纤维细胞的分化，进而促进叶状肿瘤恶性转化，揭示CCL18在叶状肿瘤恶性进展过程中的作用和临床意义，本课题的完成为遏制叶状肿瘤复发和转移提供新的思路和新的靶点。