Abstract
Perineural invasion (PNI) is a typical feature of pancreatic ductal adenocarcinoma (PDAC), which occurs in most cases. The embryonic protein Nodal plays a critical role in embryonic neural development and is overexpressed in human pancreatic cancer. In this study, we explored the contribution of Nodal to pancreatic cancer PNI and progression. We evaluated the function of Nodal in PNI by coculturing rat dorsal root ganglia and pancreatic cancer cells in vitro and performing cellular and molecular biology assays. The results illustrate that Nodal upregulates NGF (nerve growth factor), BDNF (brain-derived neurotrophic factor), and GDNF (glial cell line-derived neurotrophic factor) expression in pancreatic cancer cells and promotes cancer cell migration/invasion. Furthermore, in the in vitro 3D PNI model, Nodal enhances nerve outgrowth to pancreatic cancer cell colonies. Our study indicates that Nodal participates in tumor invasion by mediating neural and tumor cell signaling interactions, and inhibiting the expression of Nodal represents a potential strategy for targeting PNI in pancreatic cancer therapy.
Highlights
Pancreatic cancer (PC) is one of the most lethal cancers with a dismal 5-year survival rate of about 10% [1]
To determine whether Nodal affects the expression of neurotrophins (NGF, BDNF, and Glial cell line-derived neurotrophic factor transforming growth factor (TGF) (GDNF)) and matrix metalloproteinases (MMPs)-9 in pancreatic cancer cells, Panc-1 and BxPC-3 cells were treated with recombinant mature human Nodal (rhNodal) (0, 50, and 100 μM) for 24 h
Western blot analysis was used to evaluate Nerve growth factor BDNF (NGF), BDNF, GDNF, and MMP-9 protein expression in pancreatic cancer cells. e results revealed that rhNodal increased the expression levels of NGF, BDNF, GDNF, and MMP-9 in a dose-dependent manner (Figure 2(a))
Summary
Pancreatic cancer (PC) is one of the most lethal cancers with a dismal 5-year survival rate of about 10% [1]. Pancreatic ductal adenocarcinoma (PDAC) is the most common histological type with highly invasive and metastatic properties. Its poor prognosis is due to late diagnosis, early metastasis, and limited treatment options, which result in roughly equal mortality and morbidity in PC patients [2, 3]. Surgical resection is considered the only possible cure for PC, only 20% of pancreatic cancer patients can undergo curative resection [4]. Postoperative recurrence is the main factor leading to surgical failure, which occurs in up to 60% of patients. The median overall survival is only 11 months [5, 6]
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