Research Papers:

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

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

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Oncotarget. 2016; 7:18146-18158. https://doi.org/10.18632/oncotarget.7776

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Liang Han1, Jiguang Ma2, Wanxing Duan1, Lun Zhang1, Shuo Yu1, Qinhong Xu1, Jianjun Lei1, Xuqi Li3, Zheng Wang1, Zheng Wu1, Jason H. Huang4,5, Erxi Wu4,6, Qingyong Ma1, Zhenhua Ma1

1Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China

2Department of Anesthesiology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China

3Department of General Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China

4Department of Neurosurgery, Baylor Scott and White Health Care, Temple, TX, 76508, USA

5Department of Surgery, Texas A & M College of Medicine, Temple, TX, 76504, USA

6Department of Pharmaceutical Sciences, Texas A & M Health Science Center, College Station, TX, 77843, USA

Correspondence to:

Erxi Wu, e-mail: Erxi.Wu@BSWHealth.org

Qingyong Ma, e-mail: qyma56@mail.xjtu.edu.cn

Zhenhua Ma, e-mail: mzh@mail.xjtu.edu.cn

Keywords: pancreatic cancer, pain, pancreatic stellate cells, sHH

Received: September 12, 2015     Accepted: January 05, 2016     Published: February 27, 2016


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.

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