伊马替尼抑制肿瘤相关巨噬细胞M2型极化抗乳腺癌转移的作用及机制研究

Breast cancer is the leading cause of death in females in the worldwide. Among the operable breast cancer patients, there is still a chance of 20 – 30 % developing metastasis eventually. Due to the complexity of metastatic breast cancer, neither targeted therapy, endocrine therapy nor chemotherapy gained satisfied clinical responses. Therefore, the exploration of novel compounds that potently inhibit metastatic breast cancer through deeper understanding of the underlying mechanisms in metastatic breast cancer is considered of extremely importance. Tumor associated macrophages (TAM) are the most frequently found inflammatory cells in tumor stroma. To be noticed, M2 type of TAM are able to promote agiogenesis and even tumor metastasis. In our previous work, we found that Imatinib significantly inhibited M2 type of TAM. By using MMTV-PyVT transgenic mice model, we found that Imatinib obviously diminished pulmonary metastasis comparing untreated mice, probably through the inhibition of M2 polarization via AMPK-STAT6 pathway. On the basis of previous work, we will first establish the effect of Imatinib on M2 type of TAM, and then study the critical role of M2 inhibition in metastatic breast cancer. Further, we will explore the regulatory role of AMPK-STAT6 signaling pathway in M2 type of TAM, in order to illustrate the underlying mechanisms and broaden the clinical application of Imatinib in metastatic breast cancer.

乳腺癌居中国女性肿瘤发病率之首，约25%的可手术乳腺癌经根治性手术后仍发生疾病转移。由于乳腺癌转移起因复杂，无论是内分泌、靶向或是化疗的疗效都十分有限。因此，从探索乳腺癌转移机制着手，发现新的有效抑制乳腺癌转移的药物备受关注。肿瘤相关巨噬细胞(TAM)是肿瘤间质中数量最多的炎性细胞，其中M2型TAM具有促肿瘤细胞转移的功能。我们前期工作发现，伊马替尼可显著抑制TAM的M2型极化。采用乳腺癌MMTV-PyVT转基因小鼠模型，发现伊马替尼明显减少乳腺癌的肺转移灶，可能与其调控AMPK和STAT6的磷酸化水平发挥抑制TAM M2型极化的功能相关。在此基础之上，本项目将首先明确伊马替尼对TAM M2型极化的影响，进而确立伊马替尼抑制TAM M2型极化在抗乳腺癌转移中的作用和地位，阐明AMPK-STAT6信号轴在TAM M2型极化中的调控机制，为拓展伊马替尼在抗乳腺癌转移方面的临床应用提供科学依据。

近年来，越来越多的研究发现肿瘤组织中的巨噬细胞浸润和肿瘤恶性程度、预后以及复发密切相关。值得关注的是，M2型巨噬细胞的增多可能与肺癌、胃癌、乳腺癌患者的不良预后呈显著的正相关。这些研究提示，M2型肿瘤相关巨噬细胞的存在可能促进了肿瘤的转移。本研究中，我们首先采用IL-13或IL-4诱导巨噬细胞的M2型极化，伊马替尼处理后可以显著降低CD206、Arg1、Mgl2、Mrc1等M2型特有的标志物，从而我们认为伊马替尼可以有效抑制巨噬细胞的M2型极化。机制研究发现，伊马替尼能够抑制STAT6的磷酸化水平以及核内转运。在体内实验中，伊马替尼显著减少lewis肺癌的转移灶数量，同时并不影响肿瘤体积。在刨取的肿瘤和肺组织中，伊马替尼处理组的M2型巨噬细胞比例显著较空白对照组低。因此，我们发现伊马替尼可以通过抑制巨噬细胞的M2型极化，发挥其抑制lewis肺癌转移的功能。