Stromal-derived factor-1α/CXCL12-CXCR4 chemotactic pathway promotes perineural invasion in pancreatic cancer.
Stromal-derived factor-1α/CXCL12-CXCR4 chemotactic pathway promotes perineural invasion in pancreatic cancer.
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基质衍生因子-1α/CXCL12-CXCR4 趋化途径促进胰腺癌神经周围浸润
DOI：
10.18632/oncotarget.3069
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发表时间：
2015-03-10
期刊：
影响因子：
--
通讯作者：
Ma Q
中科院分区：
文献类型：
--
作者：
Xu Q;Wang Z;Chen X;Duan W;Lei J;Zong L;Li X;Sheng L;Ma J;Han L;Li W;Zhang L;Guo K;Ma Z;Wu Z;Wu E;Ma Q
神经浸润（PNI）被认为是胰腺癌细胞转移扩散的另一种途径;然而，导致PNI的分子变化仍然知之甚少。在这项研究中，我们发现CXCL 12/CXCR 4轴在胰腺癌细胞对局部周围神经的嗜性中起着关键作用。免疫组化结果显示，在78例胰腺癌标本中，CXCR 4升高与PNI相关。采用体外和体内PNI模型研究CXCL 12/CXCR 4信号通路在PNI进展和发病机制中的作用。结果表明，CXCL 12/CXCR 4轴的激活显著增加胰腺癌细胞的侵袭，并促进背根神经节的生长。来源于外周神经的CXCL 12以旁分泌方式刺激CXCR 4阳性癌细胞的侵袭和趋化迁移，最终导致PNI。体内分析显示，激活的信号传导的消除抑制了肿瘤生长和坐骨神经向脊髓的侵袭。这些数据表明，CXCL 12/CXCR 4轴可能是一个新的治疗靶点，以防止胰腺癌的神经周围扩散。
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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