中国学者发现间充质干细胞促进乳腺癌转移新机制

中国学者发现间充质干细胞促进乳腺癌转移新机制
2016年7月4日，英国《自然》旗下《癌基因》在线发表中国科学院上海生命科学研究院、上海交通大学医学院、中国科学院大学、罗格斯-罗伯特·伍德·约翰逊医学院、新泽西儿童卫生研究所、苏州大学附属第一医院、苏州大学转化医学研究院的研究成果，阐述了肿瘤坏死因子TNFα激活的间充质干细胞通过招引中性粒细胞促进肿瘤转移的新机制。

间充质干细胞是一种广泛存在于机体大部分组织中的成体干细胞。

除了具有自我更新和分化能力外，间充质干细胞还具有强大的免疫调节能力。

在肿瘤发生时，间充质干细胞可从骨髓等组织器官迁移至肿瘤微环境中，调控肿瘤发生、发展。

前期研究发现肿瘤中的间充质干细胞通过分泌大量趋化因子如CCL2、CCL7、CCL12等，招引单核细胞、巨噬细胞到达肿瘤部位，促进肿瘤生长。

此外，肿瘤部位大量存在的肿瘤坏死因子α可激活间充质干细胞，使其具有与肿瘤间充质干细胞相似的调节单核细胞和巨噬细胞的能力以及促肿瘤生长的特性。

然而，间充质干细胞调控肿瘤转移的机制尚未阐明。

该研究发现，肿瘤坏死因子α激活的间充质干细胞具有促进乳腺癌转移的能力。

间充质干细胞在肿瘤坏死因子α激活后会上调多种趋化因子的表达，包括CCL5、CCR2配体以及CXCR2配体。

利用CCL5基因敲除小鼠来源的间充质干细胞或CCR2抑制剂均并不能阻断肿瘤坏死因子α激活间充质干细胞的促肿瘤转移能力。

然而，阻断CXCR2却可显著抑制肿瘤坏死因子α激活间充质干细胞的促肿瘤转移能力。

趋化因子受体CXCR2主要表达在中性粒细胞上，肿瘤坏死因子α激活的间充质干细胞借以分泌的高水平CXCR2配体（CXCL1，CXCL2和CXCL5）招引中性粒细胞至肿瘤部位。

此外，特异性去除中性粒细胞可抑制激活间充质干细胞的促转移能力。

研究发现，CXCR2阳性中性粒细胞可与肿瘤细胞相互作用，促进促肿瘤转移相关基因在肿瘤细胞上的表达。

更重要的是，在乳腺癌患者的组织样本分析中发现相似的
基因变化模式。

该研究不仅揭示了炎症因子调控间充质干细胞促进肿瘤转移的新机制，也为靶向调控间充质干细胞介导中性粒细胞趋化能力应用于乳腺癌治疗提供了新的思路。

Oncogene. 2016 Jul 4. [Epub ahead of print]
TNFα-activated mesenchymal stromal cells promote breast cancer metastasis by recruiting CXCR2+ neutrophils.
Yu PF, Huang Y, Han YY, Lin LY, Sun WH, Rabson AB, Wang Y, Shi YF.
Shanghai Institutes for Biological Sciences/Shanghai Jiao Tong University School of Medicine, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China; Child Health Institute of New Jersey, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA; The First Affiliated Hospital of Soochow University, Institutes for Translational Medicine, Soochow University, Suzhou, China.
Mesenchymal stromal cells (MSCs) tend to infiltrate into tumors and form a major component of the tumor microenvironment. Our previous work demonstrated that tumor necrosis fact or α (TNFα)-activated MSCs significantly promoted tumor growth. However, the role of TNFα-treated MSCs in tumor metastasis remains elusive. Employing a lung metastasis model of murine breast cancer, we found that TNFα-activated MSCs strikingly enhanced tumor metastasis compared with normal MSCs. We analyzed the chemokine profiles and found that the expression of CCL5, CCR2 and CXCR2 ligands were enhanced in TNFα-activated MSCs. Using genetic or pharmacological strategies to inhibit CCL5 or CCR2, we demonstrated that CCL5 and CCR2 ligands were indispensable in supporting TNFα-activated MSCs to promote tumor metastasis. Analysis of immune cells revealed that CXCR2 ligands (CXCL1, CXCL 2 and
CXCL5) expressed by TNFα-activated MSCs efficiently recruited CXCR2+ neutrophils into tumor. These neutrophils were responsible for the pro-metastatic effect of MSCs since inhibition of this chemotaxis abolished increased neutrophil recruitment and tumor metastasis. The interaction between neutrophils and tumor cells resulted in markedly elevated metastasis-related genes by tumor cells, including CXCR4, CXCR7, MMP12, MMP13, IL-6 and TGFβ. Importantly, in IL8high human breast cancer samples, we also observed similar alterations of gene expression. Collectively, our findings de monstrate that TNFα-activated MSCs promote tumor metastasis via CXCR2+ neutrophil recruitment.
PMID: 27375023
DOI: 10.1038/onc.2016.217。