title: Sonic hedgehog paracrine signaling activates stromal cells to promote perineural invasion in pancreatic cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Departments of Hepatobiliary Surgery, General Surgery, and.
authors.forename: Xuqi
authors.initials: X
authors.lastname: Li
authors.affiliation: Departments of Hepatobiliary Surgery.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Departments of Hepatobiliary Surgery, qyma56@mail.xjtu.edu.cn kepxie@mdanderson.org.
authors.forename: Qingyong
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Departments of Hepatobiliary Surgery.
authors.forename: Qinhong
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Departments of Hepatobiliary Surgery.
authors.forename: Han
authors.initials: H
authors.lastname: Liu
authors.affiliation: Departments of Hepatobiliary Surgery.
authors.forename: Wanxing
authors.initials: W
authors.lastname: Duan
authors.affiliation: Departments of Hepatobiliary Surgery.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Lei
authors.affiliation: Oncology, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi, China;
authors.forename: Jiguang
authors.initials: J
authors.lastname: Ma
authors.affiliation: Departments of Hepatobiliary Surgery.
authors.forename: Xiu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Departments of Hepatobiliary Surgery.
authors.forename: Shifang
authors.initials: S
authors.lastname: Lv
authors.affiliation: Departments of Hepatobiliary Surgery.
authors.forename: Liang
authors.initials: L
authors.lastname: Han
authors.affiliation: Departments of Hepatobiliary Surgery.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Departments of Hepatobiliary Surgery.
authors.forename: Jian
authors.initials: J
authors.lastname: Guo
authors.affiliation: Departments of Hepatobiliary Surgery.
authors.forename: Kun
authors.initials: K
authors.lastname: Guo
authors.affiliation: Departments of Hepatobiliary Surgery.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota; and.
authors.forename: Erxi
authors.initials: E
authors.lastname: Wu
authors.affiliation: Department of Gastroenterology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas qyma56@mail.xjtu.edu.cn kepxie@mdanderson.org.
authors.forename: Keping
authors.initials: K
authors.lastname: Xie
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D010179:Pancreas / Q000378:metabolism / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D058954:Pancreatic Stellate Cells / Q000378:metabolism / Q000473:pathology*; D019899:Paracrine Communication; D010524:Peripheral Nervous System Neoplasms / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D053823:Hedgehog Proteins; C509239:SHH protein, human