Stromal-derived factor-1α/CXCL12-CXCR4 chemotactic pathway promotes perineural invasion in pancreatic cancer
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Qinhong Xu1, Zheng Wang1, Xin Chen1, Wanxing Duan1, Jianjun Lei1, Liang Zong1, Xuqi Li3, Liang Sheng1, Jiguang Ma2, Liang Han1, Wei Li1, Lun Zhang1, Kun Guo1, Zhenhua Ma1, Zheng Wu1, Erxi Wu4 and Qingyong Ma1
1 Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an 710061, Shaanxi, China
2 Department of Oncology, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an 710061, Shaanxi, China
3 Department of General Surgery, First Affiliated Hospital of Medical College, Xi’an Jiaotong University, Xi’an 710061, Shaanxi, China
4 Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA
Qingyong Ma, email:
Zheng Wang, email:
Keywords: CXCL12/CXCR4 axis, Perineural Invasion, Tumor Microenvironment, Pancreatic Cancer
Received: September 22, 2014 Accepted: December 17, 2014 Published: December 26, 2014
Perineural invasion (PNI) is considered as an alternative route for the metastatic spread of pancreatic cancer cells; however, the molecular changes leading to PNI are still poorly understood. In this study, we show that the CXCL12/CXCR4 axis plays a pivotal role in the neurotropism of pancreatic cancer cells to local peripheral nerves. Immunohistochemical staining results revealed that CXCR4 elevation correlated with PNI in 78 pancreatic cancer samples. Both in vitro and in vivo PNI models were applied to investigate the function of the CXCL12/CXCR4 signaling in PNI progression and pathogenesis. The results showed that the activation of the CXCL12/CXCR4 axis significantly increased pancreatic cancer cells invasion and promoted the outgrowth of the dorsal root ganglia. CXCL12 derived from the peripheral nerves stimulated the invasion and chemotactic migration of CXCR4-positive cancer cells in a paracrine manner, eventually leading to PNI. In vivo analyses revealed that the abrogation of the activated signaling inhibited tumor growth and invasion of the sciatic nerve toward the spinal cord. These data indicate that the CXCL12/CXCR4 axis may be a novel therapeutic target to prevent the perineural dissemination of pancreatic cancer.
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