A research article titled “Downregulation of CXCL12 in Mesenchymal Stromal Cells by TGFβ Promotes Breast Cancer Metastasis” was published online in the journal of Oncogene on September 26, 2016, reporting a novel regulatory network among transforming growth factor β (TGFβ), CXCL12, mesenchymal stromal cells (MSCs), and tumour cells during tumour metastasis.
MSCs are one of major components of the tumour microenvironment (TME). Recent studies have shown that the interplay between tumour MSCs and inflammatory factors is important in regulating tumour progression. Among these tumour-associated inflammatory factors, TGFβ is regarded as a key determinant of malignancy.
By employing a lung metastasis model of a murine breast cancer, a team led by Dr. SHI Yufang and Dr. WANG Ying at the Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences discovered that the prometastatic effect of MSCs was dependent on their response to TGFβ.
In the presence of TGFβ, the otherwise highly produced CXCL12 by MSCs was dramatically inhibited. In TGFβ-unresponsive MSCs, knockdown of CXCL12 can restore their ability to promote tumour metastasis. By analyzing the expression of CXCL12 receptors, CXCR4 and CXCR7, on breast cancer cells, it was found that CXCR7 expression on tumour cells could be downregulated by the presence of CXCL12. When CXCR7 was silenced in breast cancer cells, their metastatic ability was inhibited. Therefore, sustained expression of CXCL12 by MSCs in the primary tumour site inhibits metastasis through reduction of CXCR7, while, in the presence of TGFβ, this CXCL12 effect of MSCs on tumour cells is relieved. Such elevated CXCR7 and depressed CXCL12 expression levels were prominent features of clinical breast cancer lesions and were related significantly with poor survival.
These findings reveal a novel mechanism of MSCs in dictating tumour metastasis.
This work was mainly supported by the Ministry of Science and Technology of China, the National Natural Science Foundation of China and the Chinese Academy of Sciences.
Prof. Yufang Shi or Dr. Ying Wang
Institute of Health sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine,
Shanghai 200031, China.
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