Pancreatic Stellate Cells Facilitate Perineural Invasion of Pancreatic Cancer via HGF/c-Met Pathway

Abstract

Pancreatic cancer (PC) is a highly lethal cancer that has a strong ability for invasion and metastasis, poor prognosis, and a stubbornly high death rate due to late diagnosis and early metastasis. Therefore, a better understanding of the mechanisms of metastasis should provide novel opportunities for therapeutic purposes. As a route of metastasis in PC, perineural invasion (PNI) occurs frequently; however, the molecular mechanism of PNI is still poorly understood. In this study, we show that the hepatocyte growth factor (HGF)/c-Met pathway plays a vital role in the PNI of PC. We found that HGF promotes PC cell migration and invasion by activating the HGF/c-Met pathway, and enhances the expression of nerve growth factor (NGF) and matrix metalloproteinase-9 (MMP9) in vitro. Furthermore, HGF significantly increased PC cell invasion of the dorsal root ganglia (DRG) and promoted the outgrowth of DRG in cocultured models of PC cells and DRG. In contrast, the capacity for invasion and the phenomenon of PNI in PC cells were reduced when the HGF/c-Met pathway was blocked by siRNA. In conclusion, PSCs facilitate PC cell PNI via the HGF/c-Met pathway. Targeting the HGF/c-Met signaling pathway could be a promising therapeutic strategy for PC.

Crosstalk between Tumor and Stromal Cells in Pancreatic Ductal Adenocarcinoma

“…A common adverse feature of pancreatic cancer is neural invasion (NI) [ 90 ]. NI is the pathological process in which cancer cells invade through the nerve or its surroundings and is generally associated with a poor prognosis [ 90 , 91 ]. Studies in patients have revealed that tumors with high nerve growth factor (NGF) expression levels exhibit more frequent NI [ 92 ].…”

“…In vitro experiments revealed that CAFs secrete HGF, which subsequently increases the expression of NGF in cancer cells. In the presence of CAF-conditioned media, pancreatic cancer cells were able to successfully migrate towards dorsal root ganglia (DRG), whereas knock-down of NGF or HGF significantly reduced the migration, highlighting the importance of CAFs in NI [ 91 , 93 ].…”

Targeting HGF/c-MET Axis in Pancreatic Cancer

“…Additionally, this HGF-induced FAK activation also upregulates MMP-1, MMP-9, MMP-14 (all of these MMPs play an important role in cell invasion, thus increasing invasiveness of cancer) in gallbladder, prostate, and liver cancers [63][64][65]. Recent studies have also demonstrated that PSCs facilitate perineural invasion of pancreatic cancer and this process is mediated via the HGF/c-MET pathway [66].…”

The Role of Stellate Cells in Pancreatic Ductal Adenocarcinoma: Targeting Perspectives

“…Li et al demonstrated that activated PSCs induced neurite outgrowth towards PCCs and promoted neural invasion of PCCs ( 143 ). More recently, Nan et al reported that PSCs promoted the perineural invasion of PCCs via the HGF/c-Met pathway ( 67 ). In addition, Han et al reported that PSCs contributed to pain in PDAC by PSC-induced secretion of pain factors from dorsal root ganglia ( 144 ).…”