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

Liang Han,Jiguang Ma,Shuo Yu,Qingyong Ma,Erxi Wu,Jason H Huang,Lun Zhang,Xuqi Li,Zhenhua Ma,Jianjun Lei,Zheng Wu,Wanxing Duan,Zheng Wang,Qinhong Xu

doi:10.18632/oncotarget.7776

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.

Highlights

Abdominal pain is an important clinical symptom of pancreatic cancer (PC) that is characterized by intermittent or persistent pain and contributes to a poor quality of life in PC patients [1, 2]
We demonstrated that nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) were obviously increased in pancreatic stellate cells (PSCs) treated with media from PC cell lines that overexpress sonic hedgehog (sHH), but this increased expression could be reversed by cyclopamine or siRNA against sHH (Figure 4A and 4B) (p < 0.05)
We attempt to provide some understanding by studying the relationship of PSCs, the sHH signaling pathway and neurotrophic factors

Summary

Introduction

Abdominal pain is an important clinical symptom of pancreatic cancer (PC) that is characterized by intermittent or persistent pain and contributes to a poor quality of life in PC patients [1, 2]. Some patients present with abdominal pain, in the early stages of the disease, but most patients experience pain in advanced stages [3]. There is increasing evidence that PC pain is triggered by pancreatic neuropathy [4]. Recent studies show transient receptor potential vanilloid 1 (TRPV1), a nonselective cation channel with a preference for calcium, is involved in pancreatic pain [5,6,7]. The activation of TRPV1 in neurons induces the secretion of SP and CGRP and induces neuropathic pain in the neurons of the pancreas or dorsal root ganglia (DRG) [10, 11]. In a study on pancreatitis, quantified pain by stimulating the abdomen with von Frey hairs, elevated expression of SP www.impactjournals.com/oncotarget and CGRP was observed in DRG [12]. TRPV1 and the pain-relative factors may share more interactions in the process of PC pain

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Results

Conclusion