title: Pancreatic stellate cells contribute pancreatic cancer pain via activation of sHH signaling pathway.
abstract: Abdominal pain is a critical clinical symptom in pancreatic cancer (PC) that affects the quality of life for PC patients. However, the pathogenesis of PC pain is largely unknown. In this study, we show that PC pain is initiated by the sonic hedgehog (sHH) signaling pathway in pancreatic stellate cells (PSCs), which is activated by sHH secreted from PC cells, and then, neurotrophic factors derived from PSCs mediate the pain. The different culture systems were established in vitro, and the expression of sHH pathway molecules, neurotrophic factors, TRPV1, and pain factors were examined. Capsaicin-evoked TRPV1 currents in dorsal root ganglion (DRG) neurons were examined by the patch-clamp technique. Pain-related behavior was observed in an orthotopic tumor model. sHH and PSCs increased the expression and secretion of TRPV1, SP, and CGRP by inducing NGF and BDNF in a co-culture system, also increasing TRPV1 current. But, suppressing sHH pathway or NGF reduced the expression of TRPV1, SP, and CGRP. In vivo, PSCs and PC cells that expressed high levels of sHH could enhance pain behavior. Furthermore, the blockade of NGF or TRPV1 significantly attenuated the pain response to mechanical stimulation compared with the control. Our results demonstrate that sHH signaling pathway is involved in PC pain, and PSCs play an essential role in the process greatly by inducing NGF.
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Anesthesiology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Jiguang
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Wanxing
authors.initials: W
authors.lastname: Duan
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Lun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Shuo
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Qinhong
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Lei
authors.affiliation: Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Xuqi
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Neurosurgery, Baylor Scott and White Health Care, Temple, TX, 76508, USA.|Department of Surgery, Texas A & M College of Medicine, Temple, TX, 76504, USA.
authors.forename: Jason H
authors.initials: JH
authors.lastname: Huang
authors.affiliation: Department of Neurosurgery, Baylor Scott and White Health Care, Temple, TX, 76508, USA.|Department of Pharmaceutical Sciences, Texas A & M Health Science Center, College Station, TX, 77843, USA.
authors.forename: Erxi
authors.initials: E
authors.lastname: Wu
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Qingyong
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Ma
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000096:biosynthesis / Q000378:metabolism*; D000072716:Cancer Pain / Q000378:metabolism*; D002211:Capsaicin / Q000378:metabolism; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D005727:Ganglia, Spinal / Q000502:physiology; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020932:Nerve Growth Factor / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism*; D010179:Pancreas / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000473:pathology*; D058954:Pancreatic Stellate Cells / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015398:Signal Transduction / Q000502:physiology; D013373:Substance P / Q000096:biosynthesis / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D053823:Hedgehog Proteins; C502240:NGF protein, human; D009414:Nerve Growth Factors; C509239:SHH protein, human; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D013373:Substance P; C579455:BDNF protein, human; D020932:Nerve Growth Factor; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin
keywords: pain; pancreatic cancer; pancreatic stellate cells; sHH