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论文题目: Downregulation of CXCL12 in mesenchymal stromal cells by TGF beta promotes breast cancer metastasis
英文论文题目: Downregulation of CXCL12 in mesenchymal stromal cells by TGF beta promotes breast cancer metastasis
第一作者: Yu, PF; Huang, Y; Xu, CL; Lin, LY; Han, YY; Sun, WH; Hu, GH; Rabson, AB; Wang, Y; Shi, YF
英文第一作者: Yu, PF; Huang, Y; Xu, CL; Lin, LY; Han, YY; Sun, WH; Hu, GH; Rabson, AB; Wang, Y; Shi, YF
联系作者: Wang, Y; Shi, YF (reprint author), Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Biol Sci, Key Lab Stem Cell Biol,Inst Hlth Sci, 320 Yueyang Rd, Shanghai 200031, Peoples R China.
英文联系作者: Wang, Y; Shi, YF (reprint author), Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Biol Sci, Key Lab Stem Cell Biol,Inst Hlth Sci, 320 Yueyang Rd, Shanghai 200031, Peoples R China.
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发表年度: 2017
卷: 36
期: 6
页码: 840-849
摘要: Mesenchymal stromal cells (MSCs) are one of major components of the tumour microenvironment. Recent studies have shown that MSC tumour residence and their close interactions with inflammatory factors are important factors that affect tumour progression. Among tumour-associated inflammatory factors, transforming growth factor beta (TGF beta) is regarded as a key determinant of malignancy. By employing a lung metastasis model of a murine breast cancer, we show here that the prometastatic effect of MSCs was dependent on their response to TGF beta. Interestingly, we found that MSC-produced CXCL12, an important chemokine in tumour metastasis, was markedly inhibited by TGF beta. Furthermore, silencing of CXCL12 in TGF beta-unresponsive MSCs restored their ability to promote tumour metastasis. We found that 4T1 breast cancer cells expressed high levels of CXCR7, but not of CXCR4, both of which are CXCL12 receptors. In presence of CXCL12, CXCR7 expression on tumour cells was decreased. Indeed, when CXCR7 was silenced in breast cancer cells, their metastatic ability was inhibited. Therefore, our data demonstrated that sustained expression of CXCL12 by MSCs in the primary tumour site inhibits metastasis through reduction of CXCR7, while, in the presence of TGF beta, this CXCL12 effect of MSCs on tumour cells is relieved. Importantly, elevated CXCR7 and depressed CXCL12 expression levels were prominent features of clinical breast cancer lesions and were related significantly with poor survival. Our findings reveal a novel mechanism of MSC effects on malignant cells through which crosstalk between MSCs and TGF beta regulates tumour metastasis.
英文摘要: Mesenchymal stromal cells (MSCs) are one of major components of the tumour microenvironment. Recent studies have shown that MSC tumour residence and their close interactions with inflammatory factors are important factors that affect tumour progression. Among tumour-associated inflammatory factors, transforming growth factor beta (TGF beta) is regarded as a key determinant of malignancy. By employing a lung metastasis model of a murine breast cancer, we show here that the prometastatic effect of MSCs was dependent on their response to TGF beta. Interestingly, we found that MSC-produced CXCL12, an important chemokine in tumour metastasis, was markedly inhibited by TGF beta. Furthermore, silencing of CXCL12 in TGF beta-unresponsive MSCs restored their ability to promote tumour metastasis. We found that 4T1 breast cancer cells expressed high levels of CXCR7, but not of CXCR4, both of which are CXCL12 receptors. In presence of CXCL12, CXCR7 expression on tumour cells was decreased. Indeed, when CXCR7 was silenced in breast cancer cells, their metastatic ability was inhibited. Therefore, our data demonstrated that sustained expression of CXCL12 by MSCs in the primary tumour site inhibits metastasis through reduction of CXCR7, while, in the presence of TGF beta, this CXCL12 effect of MSCs on tumour cells is relieved. Importantly, elevated CXCR7 and depressed CXCL12 expression levels were prominent features of clinical breast cancer lesions and were related significantly with poor survival. Our findings reveal a novel mechanism of MSC effects on malignant cells through which crosstalk between MSCs and TGF beta regulates tumour metastasis.
刊物名称: ONCOGENE
英文刊物名称: ONCOGENE
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学科: Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity
英文学科: Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity
影响因子: 7.519
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论文类别: Article
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