Pancreatic stellate cells contribute pancreatic cancer pain via activation of sHH signaling pathway

Oncotarget. 2016 Apr 5;7(14):18146-58. doi: 10.18632/oncotarget.7776.


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.

Keywords: pain; pancreatic cancer; pancreatic stellate cells; sHH.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / metabolism
  • Calcitonin Gene-Related Peptide / biosynthesis
  • Calcitonin Gene-Related Peptide / metabolism*
  • Cancer Pain / metabolism*
  • Capsaicin / metabolism
  • Cell Line, Tumor
  • Coculture Techniques
  • Ganglia, Spinal / physiology
  • Hedgehog Proteins / metabolism*
  • Humans
  • Mice
  • Mice, Nude
  • Nerve Growth Factor / metabolism
  • Nerve Growth Factors / metabolism*
  • Pancreas / pathology
  • Pancreatic Neoplasms / pathology*
  • Pancreatic Stellate Cells / metabolism*
  • Patch-Clamp Techniques
  • Signal Transduction / physiology
  • Substance P / biosynthesis
  • Substance P / metabolism*
  • TRPV Cation Channels / biosynthesis
  • TRPV Cation Channels / metabolism*


  • Brain-Derived Neurotrophic Factor
  • Hedgehog Proteins
  • NGF protein, human
  • Nerve Growth Factors
  • SHH protein, human
  • TRPV Cation Channels
  • TRPV1 protein, human
  • Substance P
  • BDNF protein, human
  • Nerve Growth Factor
  • Calcitonin Gene-Related Peptide
  • Capsaicin