Stem cell autocrine CXCL12/CXCR4 stimulates invasion and metastasis of esophageal cancer
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Xingwei Wang1,2, Yan Cao1, Shirong Zhang1, Zhihui Chen1, Ling Fan1, Xiaochun Shen1, Shiwen Zhou2 and Dongfeng Chen1
1Department of Gastroenterology, The Third Affiliated Hospital, Third Military Medical University, Chongqing 400042, China
2Department of Base for Drug Clinical Trial, The Second Affiliated Hospital, Third Military Medical University, Chongqing 400037, China
Dongfeng Chen, email: [email protected]
Keywords: esophageal cancer, esophageal cancer stem cells, CXCL12, CXCR4, metastasis
Received: August 02, 2016 Accepted: December 01, 2016 Published: February 10, 2017
Esophageal cancer is one of the most common malignant tumors of the digestive tract. The greatest obstacle to the curing of esophageal cancer is its propensity to spread and metastasize. Esophageal cancer stem cells are considered the source for recurrence and metastasis of the tumors. While clinical evidence suggested that continuous up-regulation of CXCL12/CXCR4 was significantly associated with poor prognosis in patients with esophageal cancer, but the role and mechanism of CXCL12/CXCR4 in the invasion and metastasis of esophageal cancer has not been reported by far. This study found that esophageal cancer stem cells not only autocrine a great amount of CXCL12, but also high expression of its corresponding receptor CXCR4. Most importantly, the ability of esophageal cancer stem cells to spread and metastasize could be inhibited by blockage of CXCR4 with inhibitors or shRNA approaches both in vivo and in vitro studies. The important role of CXCL12 in the invasion and metastasis of esophageal cancer stem cells was also confirmed by loss-of-function and gain-of-function strategies. Mechanistically, we demonstrated that CXCL12/CXCR4 activated the ERK1/2 pathway and thereby ultimately maintained the characteristics of high-level invasion and metastasis of esophageal cancer stem cells. Taken together, our findings suggested that autocrine CXCL12/CXCR4 was one of the major mechanisms underlying the metastatic property of esophageal cancer stem cells through ERK1/2 signaling pathway, and might serve as a therapeutic target for esophageal cancer patients.
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