Sonic Hedgehog Paracrine Signaling Activates Stromal Cells to Promote Perineural Invasion in Pancreatic Cancer
Sonic Hedgehog Paracrine Signaling Activates Stromal Cells to Promote Perineural Invasion in Pancreatic Cancer
复制标题
Sonic Hedgehog 旁分泌信号激活基质细胞促进胰腺癌神经周围侵袭
DOI：
10.1158/1078-0432.ccr-13-3426
复制
发表时间：
2014-08-15
影响因子：
11.5
通讯作者：
Xie, Keping
中科院分区：
文献类型：
--
作者：
Li, Xuqi;Wang, Zheng;Xie, Keping
目的：胰腺癌的特征是间质结缔组织增生和神经周侵袭（PNI）。我们试图探索旁分泌Sonic Hedgehog（SHH）激活的胰腺星状细胞（PSC）在胰腺癌PNI和进展中的作用。实验设计：在这项研究中，SHH的表达动力学通过免疫组化，实时PCR和Western印迹分析在一组癌性和非肿瘤性胰腺组织和细胞中进行了研究。进行了一系列体内和体外测定以阐明由旁分泌SHH信号传导激活的PSC在胰腺癌PNI和进展中的贡献。结果如下：我们发现SHH在肿瘤细胞中的过表达参与了胰腺癌的PNI，并且是胰腺癌生物学活性的重要标志。此外，SHH在肿瘤细胞中的过表达激活基质中PSC中的hedgehog通路，而不是激活肿瘤细胞。这些活化的PSC对于促进胰腺癌细胞沿着神经轴突迁移和在癌症中神经侵袭的体外三维模型中神经向外生长至胰腺癌细胞集落是必需的。此外，在体内模型中，由旁分泌SHH激活的PSC的共植入诱导肿瘤细胞侵入躯干和沿着坐骨神经的神经功能障碍，并且还促进了正交异性异种移植肿瘤的生长、转移和PNI。结论：这些结果表明，胰腺癌细胞中SHH旁分泌信号激活的基质PSC分泌高水平的PNI相关分子，以促进胰腺癌中的PNI。临床癌症研究; 20（16）; 4326-38。©2014 AACR.
Purpose: Pancreatic cancer is characterized by stromal desmoplasia and perineural invasion (PNI). We sought to explore the contribution of pancreatic stellate cells (PSC) activated by paracrine Sonic Hedgehog (SHH) in pancreatic cancer PNI and progression. Experimental Design: In this study, the expression dynamics of SHH were examined via immunohistochemistry, real-time PCR, and Western blot analysis in a cohort of carcinomatous and nonneoplastic pancreatic tissues and cells. A series of in vivo and in vitro assays was performed to elucidate the contribution of PSCs activated by paracrine SHH signaling in pancreatic cancer PNI and progression. Results: We show that SHH overexpression in tumor cells is involved in PNI in pancreatic cancer and is an important marker of biologic activity of pancreatic cancer. Moreover, the overexpression of SHH in tumor cells activates the hedgehog pathway in PSCs in the stroma instead of activating tumor cells. These activated PSCs are essential for the promotion of pancreatic cancer cell migration along nerve axons and nerve outgrowth to pancreatic cancer cell colonies in an in vitro three-dimensional model of nerve invasion in cancer. Furthermore, the coimplantation of PSCs activated by paracrine SHH induced tumor cell invasion of the trunk and nerve dysfunction along sciatic nerves and also promoted orthotropic xenograft tumor growth, metastasis, and PNI in in vivo models. Conclusions: These results establish that stromal PSCs activated by SHH paracrine signaling in pancreatic cancer cells secrete high levels of PNI-associated molecules to promote PNI in pancreatic cancer. Clin Cancer Res; 20(16); 4326–38. ©2014 AACR.