HGF/c-Met Pathway Facilitates the Perineural Invasion of Pancreatic Cancer by Activating the MTOR/NGF Axis

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2022 Apr 22

PMID 35449152

Authors

Tao Qin

Ying Xiao

Weikun Qian

Xueni Wang

Mengyuan Gong

Qiqi Wang

Rui An

Liang Han

Wanxing Duan

Qingyong Ma

Zheng Wang

Affiliations

Soon will be listed here.

Abstract

Perineural invasion (PNI) is a pathologic feature of pancreatic cancer and is associated with poor outcomes, metastasis, and recurrence in pancreatic cancer patients. However, the molecular mechanism of PNI remains unclear. The present study aimed to investigate the mechanism that HGF/c-Met pathway facilitates the PNI of pancreatic cancer. In this study, we confirmed that c-Met expression was correlated with PNI in pancreatic cancer tissues. Activating the HGF/c-Met signaling pathway potentiated the expression of nerve growth factor (NGF) to recruit nerves and promote the PNI. Activating the HGF/c-Met signaling pathway also enhanced the migration and invasion ability of cancer cells to facilitate cancer cells invading nerves. Mechanistically, HGF/c-Met signaling pathway can active the mTOR/NGF axis to promote the PNI of pancreatic cancer. Additionally, we found that knocking down c-Met expression inhibited cancer cell migration along the nerve, reduced the damage of the sciatic nerve caused by cancer cells and protected the function of the sciatic nerve in vivo. Taken together, our findings suggest a supportive mechanism of the HGF/c-Met signaling pathway in promoting PNI by activating the mTOR/NGF axis in pancreatic cancer. Blocking the HGF/c-Met signaling pathway may be an effective target for the treatment of PNI.

Citing Articles

Spatial Transcriptomics Reveals Novel Mechanisms Involved in Perineural Invasion in Pancreatic Ductal Adenocarcinomas.

Lakis V, Chan N, Lyons R, Blackburn N, Nguyen T, Chang C Cancers (Basel). 2025; 17(5).

PMID: 40075699 PMC: 11899704. DOI: 10.3390/cancers17050852.

Xanthohumol overcomes osimertinib resistance via governing ubiquitination-modulated Ets-1 turnover.

Ma Y, Wang R, Liao J, Guo P, Wang Q, Li W Cell Death Discov. 2024; 10(1):454.

PMID: 39468027 PMC: 11519634. DOI: 10.1038/s41420-024-02220-y.

Neural Circuitries between the Brain and Peripheral Solid Tumors.

Chen X, Geng Y, Wei G, He D, Lv J, Wen W Cancer Res. 2024; 84(21):3509-3521.

PMID: 39226520 PMC: 11532784. DOI: 10.1158/0008-5472.CAN-24-1779.

Hallmarks of perineural invasion in pancreatic ductal adenocarcinoma: new biological dimensions.

Sun Y, Jiang W, Liao X, Wang D Front Oncol. 2024; 14:1421067.

PMID: 39119085 PMC: 11307098. DOI: 10.3389/fonc.2024.1421067.

Perineural Invasion in Cervical Cancer: A Hidden Trail for Metastasis.

Chen G, Sun H, Chen Y, Wang L, Song O, Zhang J Diagnostics (Basel). 2024; 14(14).

PMID: 39061654 PMC: 11275432. DOI: 10.3390/diagnostics14141517.

References

Zhu Y, Colak T, Shenoy M, Liu L, Pai R, Li C . Nerve growth factor modulates TRPV1 expression and function and mediates pain in chronic pancreatitis. Gastroenterology. 2011; 141(1):370-7. PMC: 7522725. DOI: 10.1053/j.gastro.2011.03.046. View

Nisar M, Paracha R, Arshad I, Adil S, Zeb S, Hanif R . Integrated Analysis of Microarray and RNA-Seq Data for the Identification of Hub Genes and Networks Involved in the Pancreatic Cancer. Front Genet. 2021; 12:663787. PMC: 8273913. DOI: 10.3389/fgene.2021.663787. View

Comoglio P, Trusolino L, Boccaccio C . Known and novel roles of the MET oncogene in cancer: a coherent approach to targeted therapy. Nat Rev Cancer. 2018; 18(6):341-358. DOI: 10.1038/s41568-018-0002-y. View

Elsherbiny N, Abdel-Mottaleb Y, Elkazaz A, Atef H, Lashine R, Youssef A . Carbamazepine Alleviates Retinal and Optic Nerve Neural Degeneration in Diabetic Mice via Nerve Growth Factor-Induced PI3K/Akt/mTOR Activation. Front Neurosci. 2019; 13:1089. PMC: 6838003. DOI: 10.3389/fnins.2019.01089. View

Siegel R, Miller K, Fuchs H, Jemal A . Cancer Statistics, 2021. CA Cancer J Clin. 2021; 71(1):7-33. DOI: 10.3322/caac.21654. View

Di Donato M, Cernera G, Migliaccio A, Castoria G . Nerve Growth Factor Induces Proliferation and Aggressiveness In Prostate Cancer Cells. Cancers (Basel). 2019; 11(6). PMC: 6627659. DOI: 10.3390/cancers11060784. View

Xin B, He X, Wang J, Cai J, Wei W, Zhang T . Nerve growth factor regulates CD133 function to promote tumor cell migration and invasion via activating ERK1/2 signaling in pancreatic cancer. Pancreatology. 2016; 16(6):1005-1014. DOI: 10.1016/j.pan.2016.09.005. View

Lohse I, Brothers S . Pathogenesis and Treatment of Pancreatic Cancer Related Pain. Anticancer Res. 2020; 40(4):1789-1796. PMC: 7323503. DOI: 10.21873/anticanres.14133. View

Cheng M, Lv X, Zhang C, Du W, Liu Y, Zhu L . DNMT1, a Novel Regulator Mediating mTORC1/mTORC2 Pathway-Induced NGF Expression in Schwann Cells. Neurochem Res. 2018; 43(11):2141-2154. DOI: 10.1007/s11064-018-2637-1. View

10.

Nan L, Qin T, Xiao Y, Qian W, Li J, Wang Z . Pancreatic Stellate Cells Facilitate Perineural Invasion of Pancreatic Cancer via HGF/c-Met Pathway. Cell Transplant. 2019; 28(9-10):1289-1298. PMC: 6767883. DOI: 10.1177/0963689719851772. View

11.

Derynck R, Weinberg R . EMT and Cancer: More Than Meets the Eye. Dev Cell. 2019; 49(3):313-316. PMC: 7672963. DOI: 10.1016/j.devcel.2019.04.026. View

12.

Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z . GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017; 45(W1):W98-W102. PMC: 5570223. DOI: 10.1093/nar/gkx247. View

13.

Li X, Wang Z, Ma Q, Xu Q, Liu H, Duan W . Sonic hedgehog paracrine signaling activates stromal cells to promote perineural invasion in pancreatic cancer. Clin Cancer Res. 2014; 20(16):4326-38. DOI: 10.1158/1078-0432.CCR-13-3426. View

14.

Liebig C, Ayala G, Wilks J, Berger D, Albo D . Perineural invasion in cancer: a review of the literature. Cancer. 2009; 115(15):3379-91. DOI: 10.1002/cncr.24396. View

15.

Bapat A, Hostetter G, Von Hoff D, Han H . Perineural invasion and associated pain in pancreatic cancer. Nat Rev Cancer. 2011; 11(10):695-707. DOI: 10.1038/nrc3131. View

16.

Ceyhan G, Bergmann F, Kadihasanoglu M, Altintas B, Demir I, Hinz U . Pancreatic neuropathy and neuropathic pain--a comprehensive pathomorphological study of 546 cases. Gastroenterology. 2008; 136(1):177-186.e1. DOI: 10.1053/j.gastro.2008.09.029. View

17.

Switon K, Kotulska K, Janusz-Kaminska A, Zmorzynska J, Jaworski J . Molecular neurobiology of mTOR. Neuroscience. 2016; 341:112-153. DOI: 10.1016/j.neuroscience.2016.11.017. View

18.

Pothula S, Xu Z, Goldstein D, Pirola R, Wilson J, Apte M . Targeting HGF/c-MET Axis in Pancreatic Cancer. Int J Mol Sci. 2020; 21(23). PMC: 7730415. DOI: 10.3390/ijms21239170. View

19.

Wang H, Zheng Q, Lu Z, Wang L, Ding L, Xia L . Role of the nervous system in cancers: a review. Cell Death Discov. 2021; 7(1):76. PMC: 8041826. DOI: 10.1038/s41420-021-00450-y. View

20.

March B, Faulkner S, Jobling P, Steigler A, Blatt A, Denham J . Tumour innervation and neurosignalling in prostate cancer. Nat Rev Urol. 2020; 17(2):119-130. DOI: 10.1038/s41585-019-0274-3. View