Neurotransmitter Substance P Mediates Pancreatic Cancer Perineural Invasion via NK-1R in Cancer Cells

BackgroundPerineural invasion (PNI) is an important pathologic feature of pancreatic cancer, and the incidence of PNI in pancreatic cancer is 70%-100%. PNI is associated with poor outcome, metastasis, and recurrence in pancreatic cancer patients. There are very few treatments for PNI in pancreatic cancer. Honokiol (HNK) is a natural product that is mainly obtained from Magnolia species and has been indicated to have anticancer activity. HNK also has potent neurotrophic activity and may be effective for suppressing PNI. However, the potential role of HNK in the treatment of PNI in pancreatic cancer has not been elucidated.MethodsIn our study, pancreatic cancer cells were treated with vehicle or HNK, and the invasion and migration capacities were assessed by wound scratch assays and Transwell assays. A cancer cell-dorsal root ganglion coculture model was established to evaluate the effect of HNK on the PNI of pancreatic cancer. Western blotting was used to detect markers of EMT and neurotrophic factors in pancreatic tissue. Recombinant TGF-β1 was used to activate SMAD2/3 to verify the effect of HNK on SMAD2/3 and neurotrophic factors. The subcutaneous tumor model and the sciatic nerve invasion model, which were established in transgenic engineered mice harboring spontaneous pancreatic cancer, were used to investigate the mechanism by which HNK inhibits EMT and PNI in vivo.ResultsWe found that HNK can inhibit the invasion and migration of pancreatic cancer cells. More importantly, HNK can inhibit the PNI of pancreatic cancer. The HNK-mediated suppression of pancreatic cancer PNI was partially mediated by inhibition of SMAD2/3 phosphorylation. In addition, the inhibitory effect of HNK on PNI can be reversed by activating SMAD2/3. In vivo, we found that HNK can suppress EMT in pancreatic cancer. HNK can also inhibit cancer cell migration along the nerve, reduce the damage to the sciatic nerve caused by tumor cells and protect the function of the sciatic nerve.ConclusionOur results demonstrate that HNK can inhibit the invasion, migration, and PNI of pancreatic cancer by blocking SMAD2/3 phosphorylation, and we conclude that HNK may be a new strategy for suppressing PNI in pancreatic cancer.

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Interaction of the Sympathetic Nerve with Pancreatic Cancer Cells Promotes Perineural Invasion through the Activation of STAT3 Signaling

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-12-0809 ◽

2013 ◽

Vol 12 (3) ◽

pp. 264-273 ◽

Cited By ~ 33

Author(s):

Kun Guo ◽

Qingyong Ma ◽

Junhui Li ◽

Zheng Wang ◽

Tao Shan ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Sympathetic Nerve ◽

Perineural Invasion ◽

Stat3 Signaling ◽

Pancreatic Cancer Cells

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Faculty Opinions recommendation of Endoneurial macrophages induce perineural invasion of pancreatic cancer cells by secretion of GDNF and activation of RET tyrosine kinase receptor.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717964363.793465967 ◽

2012 ◽

Author(s):

Giancarlo Vecchio ◽

Rosa Marina Melillo

Keyword(s):

Pancreatic Cancer ◽

Tyrosine Kinase ◽

Cancer Cells ◽

Perineural Invasion ◽

Tyrosine Kinase Receptor ◽

Pancreatic Cancer Cells

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Autophagic Schwann Cells Promote Perineural Invasion Mediated by the NGF/ATG7 Paracrine Pathway in Pancreatic Cancer

10.21203/rs.3.rs-892484/v1 ◽

2021 ◽

Author(s):

Wunai Zhang ◽

Rui He ◽

Wenbin Yang ◽

Yan Zhang ◽

Qinggong Yuan ◽

...

Keyword(s):

Pancreatic Cancer ◽

Schwann Cell ◽

Cancer Cells ◽

Schwann Cells ◽

Western Blotting ◽

Cell Apoptosis ◽

Perineural Invasion ◽

Nerve Fibers ◽

Therapeutic Effects ◽

Autophagy Inhibitor

Abstract BackgroundPerineural invasion (PNI) and autophagy are two common features in the tumor microenvironment of pancreatic cancer (PanCa) and have a negative effect on prognosis. Potential mediator cells and the molecular mechanism underlying their relationships need to be fully elucidated. MethodsTo investigate the autophagy of Schwann cells (SCs) in PNI, we reproduced the microenvironment of PNI by collecting clinical PNI tissue, performing sciatic nerve injection of nude mice with cancer cells and establishing a Dorsal root ganglion（DRG） coculture system with cancer cell lines. Autophagy was detected by IHC, IF, transmission electron microscopy (TEM) and western blotting assays. Apoptosis was detected by IF, TEM and western blotting. NGF targeting molecular RO 08-2750（RO） and the autophagy inhibitor Chloroquine（CQ）were utilized to evaluate the effect on autophagy and apoptosis in SCs and PanCa cells in PNI samples.ResultsSC autophagy is activated in PNI by paracrine NGF from PanCa cells. Autophagy-activated Schwann cells promote PNI through a) enhanced migration and axon guidance toward PanCa cells and b) increased chemoattraction to PanCa cells. The NGF-targeting reagent RO and autophagy inhibitor CQ inhibited Schwann cell autophagic flux and induced Schwann cell apoptosis. Moreover, RO and CQ could induce PanCa cell apoptosis and showed good therapeutic effects in the PNI model.ConclusionsPanCa cells can induce autophagy in SCs through paracrine pathways such as the NGF/ATG7 pathway. Autophagic SCs exert a "nerve-repair like effect", induce a high level of autophagy of cancer cells, provide a "beacon" for the invasion of cancer cells to nerve fibers, and induce directional growth of cancer cells. Targeting NGF and autophagy for PNI treatment can block nerve infiltration and is expected to provide new directions and an experimental basis for the research and treatment of nerve infiltration in pancreatic cancer.

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