Sonic hedgehog signaling pathway promotes pancreatic cancer pain via nerve growth factor

Abstract

Background Many patients with pancreatic cancer (PC) suffer from abdominal pain and back pain. However, the cause of pain associated with PC is largely unclear. In this study, we tested the potential influence of the sonic hedgehog (sHH) signaling pathway on PC pain. Methods Substance P (SP) and calcitonin gene-related peptide (CGRP) expression was measured in cultured PC cells and dorsal root ganglions (DRG) by real-time PCR, western blotting analysis and ELISA. Small interfering RNA transfection and plasmid constructs were used to regulate the expression of sHH in the AsPc-1 and Panc-1 cell lines. Pain-related behavior was observed in an orthotopic tumor model in nude mice. Results In this study, the results show that sHH increased the expression of SP and CGRP in DRGs in a concentration and time-dependent manner. Additionally, sHH secretion from PC cells could activate the sHH signaling pathway and, in turn, increase the expression of nerve growth factor (NGF), P75, and TrkA in DRGs. Furthermore, the sHH signaling pathway and NGF/NGF receptor contributed to pain sensitivity in a nude mouse model. Conclusion Our results demonstrate that PC pain originates from the sHH signaling pathway, and NGF mediates the pain mechanism via regulating SP and CGRP.

Tumor-infiltrating nerves create an electro-physiologically active microenvironment and contribute to treatment resistance

“…Interestingly, pain is one of the most prominent symptoms reported by patients that ultimately receive a diagnosis of late stage ovarian cancer [63-65]. A similar correlation between cancer pain, advanced disease and sensory innervation exists in pancreatic cancer where sonic hedgehog promotes signaling and initiation of pain via sensory nerves [66, 67]. Likewise, pain in recurrent or late stage cervical cancer remains a challenge [68-70].…”

CGRP: A New Endogenous Cell Stemness Maintenance Molecule

“…Further studies show that the SHH signal pathway may be regulated by CGRP on the proliferation and differentiation of lung cancer cells [ 61 , 136 ]. Pancreatic cancer cells could activate the SHH signaling pathway which increased the expression of CGRP and TRPV1 in the dorsal root ganglion in a concentration- and time-dependent manner, resulting in the pain of pancreatic cancer [ 137 , 138 ]. In a word, whether CGRP regulates cell stemness through the SHH signaling pathway needs further study.…”

Animal Models of Cancer-Related Pain: Current Perspectives in Translation

“…Immunodeficiency is required for xenograft models, which is an important component when considering the multifaceted cancer pain phenotype. While immune cells are not absent in the cancer microenvironment (Chodroff et al, (Halvorson et al, 2005b;King et al, 2008;Thudi et al, 2008;Jimenez-Andrade et al, 2010) Pancreas SW 1990, Panc1, AsPc-1, Capan1 Pancreas, bone, sciatic, flank (Wang et al, 2017;Miura et al, 2018;Han et al, 2020) Melanoma WM-127 Hindpaw (Pickering et al, 2008) Oral HSC3, HSC2 Hindpaw, tongue, floor of mouth (Pickering et al, 2008;Ye et al, 2011;Ye et al, 2012;Chodroff et al, 2016;Lam, 2016;Scheff et al, 2017) Breast MDA-MB-231-BO Bone, mammary pad (Hiraga et al, 2001;Bloom et al, 2011;Ungard et al, 2014;Zinonos et al, 2014) Allograft transplant models Hindpaw, vibrissal pad, bone, mammary pad (Medhurst et al, 2002;Zhang et al, 2005;Liu et al, 2010;Yin et al, 2010;Wang et al, 2012;Calixto-Campos et al, 2013;Lofgren et al, 2018;Appel et al,…”