The Significance of Neuropilins in Gastrointestinal Cancers
Abstract
1. Introduction
2. Neuropilins
3. Neuropilins in Colorectal Cancer
4. Neuropilins in Gastric Cancer
5. Neuropilins in Pancreatic Cancer
6. Neuropilins in Liver Cancer
7. Non-Coding RNA and NRP
8. Summary
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef]
- Song, M.; Garrett, W.S.; Chan, A.T. Nutrients, foods, and colorectal cancer prevention. Gastroenterology 2015, 148, 1244–1260.e16. [Google Scholar] [CrossRef] [PubMed]
- Duffy, M.; Lamerz, R.; Haglund, C.; Nicolini, A.; Kalousová, M.; Holubec, L.; Sturgeon, C. Tumor markers in colorectal cancer, gastric cancer and gastrointestinal stromal cancers: European group on tumor markers 2014 guidelines update. Int. J. Cancer 2014, 134, 2513–2522. [Google Scholar] [CrossRef] [PubMed]
- Ellis, L.M. The role of neuropilins in cancer. Mol. Cancer Ther. 2006, 5, 1099–1107. [Google Scholar] [CrossRef] [PubMed]
- Rizzolio, S.; Tamagnone, L. Multifaceted Role of Neuropilins in Cancer. Curr. Med. Chem. 2011, 18, 3563–3575. [Google Scholar] [CrossRef]
- Pereira, E.R.; Jones, D.; Jung, K.; Padera, T.P. The lymph node microenvironment and its role in the progression of metastatic cancer. Semin. Cell Dev. Biol. 2015, 38, 98–105. [Google Scholar] [CrossRef]
- Grünewald, F.S.; Prota, A.E.; Giese, A.; Ballmer-Hofer, K. Structure–function analysis of VEGF receptor activation and the role of coreceptors in angiogenic signaling. Biochim. Biophys. Acta (BBA)-Proteins Proteom. 2010, 1804, 567–580. [Google Scholar] [CrossRef]
- Roth, L.; Nasarre, C.; Dirrig-Grosch, S.; Aunis, D.; Crémel, G.; Hubert, P.; Bagnard, D. Transmembrane Domain Interactions Control Biological Functions of Neuropilin-1. Mol. Biol. Cell 2008, 19, 646–654. [Google Scholar] [CrossRef]
- Bielenberg, D.R.; Zetter, B.R. The Contribution of Angiogenesis to the Process of Metastasis. Cancer J. 2015, 21, 267–273. [Google Scholar] [CrossRef]
- Wang, L.; Dutta, S.K.; Kojima, T.; Xu, X.; Khosravi-Far, R.; Ekker, S.C.; Mukhopadhyay, D. Neuropilin-1 Modulates p53/Caspases Axis to Promote Endothelial Cell Survival. PLoS ONE 2007, 2, e1161. [Google Scholar] [CrossRef]
- Wild, J.R.L.; Staton, C.A.; Chapple, K.; Corfe, B.M. Neuropilins: Expression and roles in the epithelium. Int. J. Exp. Pathol. 2012, 93, 81–103. [Google Scholar] [CrossRef]
- Mendes-Da-Cruz, D.A.; Linhares-Lacerda, L.; Smaniotto, S.; Dardenne, M.; Savino, W. Semaphorins and neuropilins: New players in the neuroendocrine control of the intrathymic T-cell migration in humans. Exp. Physiol. 2012, 97, 1146–1150. [Google Scholar] [CrossRef] [PubMed]
- Grage-Griebenow, E.; Löseke, S.; Kauth, M.; Gehlhar, K.; Zawatzky, R.; Bufe, A. Anti-BDCA-4 (neuropilin-1) antibody can suppress virus-induced IFN-alpha production of plasmacytoid dendritic cells. Immunol. Cell Biol. 2007, 85, 383–390. [Google Scholar] [CrossRef] [PubMed]
- Solomon, B.D.; Mueller, C.; Chae, W.-J.; Alabanza, L.M.; Bynoe, M.S. Neuropilin-1 attenuates autoreactivity in experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA 2011, 108, 2040–2045. [Google Scholar] [CrossRef] [PubMed]
- Pan, Q.; Chanthery, Y.; Liang, W.-C.; Stawicki, S.; Mak, J.; Rathore, N.; Tong, R.K.; Kowalski, J.; Yee, S.F.; Pacheco, G.; et al. Blocking Neuropilin-1 Function Has an Additive Effect with Anti-VEGF to Inhibit Tumor Growth. Cancer Cell 2007, 11, 53–67. [Google Scholar] [CrossRef]
- Appleton, B.A.; Wu, P.; Maloney, J.; Yin, J.; Liang, W.-C.; Stawicki, S.; Mortara, K.; Bowman, K.K.; Elliott, J.M.; Desmarais, W.; et al. Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding. EMBO J. 2007, 26, 4902–4912. [Google Scholar] [CrossRef]
- Yaqoob, U.; Cao, S.; Shergill, U.; Jagavelu, K.; Geng, Z.; Yin, M.; De Assuncao, T.M.; Cao, Y.; Szabolcs, A.; Thorgeirsson, S.; et al. Neuropilin-1 stimulates tumor growth by increasing fibronectin fibril assembly in the tumor microenvironment. Cancer Res. 2012, 72, 4047–4059. [Google Scholar] [CrossRef]
- Sugahara, K.N.; Teesalu, T.; Prakash Karmali, P.; Ramana Kotamraju, V.; Agemy, L.; Greenwald, D.R.; Ruoslahti, E. Coadministration of a Tumor-Penetrating Peptide Enhances the Efficacy of Cancer Drugs. Science 2010, 328, 1031–1035. [Google Scholar] [CrossRef]
- Parikh, A.A.; Fan, F.; Liu, W.B.; Ahmad, S.A.; Stoeltzing, O.; Reinmuth, N.; Bielenberg, D.; Bucana, C.D.; Klagsbrun, M.; Ellis, L.M. Neuropilin-1 in human colon cancer: Expression, regulation, and role in induction of angiogenesis. Am. J. Pathol. 2004, 164, 2139–2151. [Google Scholar] [CrossRef]
- Fernández-Palanca, P.; Payo-Serafín, T.; Fondevila, F.; Méndez-Blanco, C.; San-Miguel, B.; Romero, M.R.; Tuñón, M.J.; Marin, J.J.G.; González-Gallego, J.; Mauriz, J.L. Neuropilin-1 as a Potential Biomarker of Prognosis and Invasive-Related Parameters in Liver and Colorectal Cancer: A Systematic Review and Meta-Analysis of Human Studies. Cancers 2022, 14, 3455. [Google Scholar] [CrossRef]
- Grandclement, C.; Pallandre, J.R.; Valmary Degano, S.; Viel, E.; Bouard, A.; Balland, J.; Remy-Martin, J.P.; Simon, B.; Rouleau, A.; Boireau, W.; et al. Neuropilin-2 expression promotes TGF-β1-mediated epithelial to mesenchymal transition in colorectal cancer cells. PLoS ONE 2011, 6, e20444. [Google Scholar] [CrossRef]
- Geretti, E.; van Meeteren, L.A.; Shimizu, A.; Dudley, A.C.; Claesson-Welsh, L.; Klagsbrun, M. A mutated soluble neuropilin-2 B domain antagonizes vascular endothelial growth factor bioactivity and inhibits tumor progression. Mol. Cancer Res. 2010, 8, 1063–1073. [Google Scholar] [CrossRef] [PubMed]
- Cao, H.; Li, Y.; Huang, L.; Bai, B.; Xu, Z. Clinicopathological Significance of Neuropilin 1 Expression in Gastric Cancer: A Meta-Analysis. Dis. Markers 2020, 2020, 4763492. [Google Scholar] [CrossRef] [PubMed]
- Yang, H.; Zhou, Y.; Wang, L.; Lv, M.; Sun, J.; Luo, Z.; He, J. Sema3A Alleviates the Malignant Behaviors of Gastric Cancer Cells by Inhibiting NRP-1. Curr. Mol. Med. 2024, 24, 931–939. [Google Scholar] [CrossRef] [PubMed]
- Wu, C.; Zeng, M.-H.; Liao, G.; Qian, K.; Li, H. Neuropilin-1 Interacts with Fibronectin-1 to Promote Epithelial–Mesenchymal Transition Progress in Gastric Cancer. OncoTargets Ther. 2020, 13, 10677–10687. [Google Scholar] [CrossRef]
- Seo, H.S.; Hyeon, J.; Song, I.H.; Lee, H.H. Relationship between neuropilin-1 expression and prognosis, according to gastric cancer histology. Histochem. J. 2020, 51, 199–208. [Google Scholar] [CrossRef]
- Jin, Q.; Ren, Q.; Chang, X.; Yu, H.; Jin, X.; Lu, X.; He, N.; Wang, G. Neuropilin-1 predicts poor prognosis and promotes tumor metastasis through epithelial-mesenchymal transition in gastric cancer. J. Cancer 2021, 12, 3648–3659. [Google Scholar] [CrossRef]
- Ding, Y.; Zhou, J.; Wang, S.; Li, Y.; Mi, Y.; Gao, S.; Xu, Y.; Chen, Y.; Yan, J. Anti-neuropilin-1 monoclonal antibody suppresses the migration and invasion of human gastric cancer cells via Akt dephosphorylation. Exp. Ther. Med. 2018, 16, 537–546. [Google Scholar] [CrossRef]
- Islam, R.; Mishra, J.; Bodas, S.; Bhattacharya, S.; Batra, S.K.; Dutta, S.; Datta, K. Role of Neuropilin-2-mediated signaling axis in cancer progression and therapy resistance. Cancer Metastasis Rev. 2022, 41, 771–787. [Google Scholar] [CrossRef]
- Roy, S.; Bag, A.K.; Dutta, S.; Polavaram, N.S.; Islam, R.; Schellenburg, S.; Banwait, J.; Guda, C.; Ran, S.; Hollingsworth, M.A.; et al. Macrophage-Derived Neuropilin-2 Exhibits Novel Tumor-Promoting Functions. Cancer Res. 2018, 78, 5600–5617. [Google Scholar] [CrossRef]
- Ilic, M.; Ilic, I. Epidemiology of pancreatic cancer. World J. Gastroenterol. 2016, 22, 9694–9705. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- McDonald, O.G. The biology of pancreatic cancer morphology. Pathology 2021, 54, 236–247. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Meng, S.; Hara, T.; Sato, H.; Tatekawa, S.; Tsuji, Y.; Saito, Y.; Hamano, Y.; Arao, Y.; Gotoh, N.; Ogawa, K.; et al. Revealing neuropilin expression patterns in pancreatic cancer: From single-cell to therapeutic opportunities (Review). Oncol. Lett. 2022, 27, 113. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Piera-Velazquez, S.; Jimenez, S.A. Endothelial to Mesenchymal Transition: Role in Physiology and in the Pathogenesis of Human Diseases. Physiol. Rev. 2019, 99, 1281–1324. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Borchardt, H.; Schulz, A.; Datta, K.; Muders, M.H.; Aigner, A. Silencing of Neuropilins and GIPC1 in pancreatic ductal adenocarcinoma exerts multiple cellular and molecular antitumor effects. Sci. Rep. 2019, 9, 15471. [Google Scholar] [CrossRef]
- Zhou, R.; Curry, J.M.; Roy, L.D.; Grover, P.; Haider, J.; Moore, L.J.; Wu, S.-T.; Kamesh, A.; Yazdanifar, M.; Ahrens, W.A.; et al. A novel association of neuropilin-1 and MUC1 in pancreatic ductal adenocarcinoma: Role in induction of VEGF signaling and angiogenesis. Oncogene 2016, 35, 5608–5618. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Matkar, P.N.; Jong, E.D.; Ariyagunarajah, R.; Prud’Homme, G.J.; Singh, K.K.; Leong-Poi, H. Jack of many trades: Multifaceted role of neuropilins in pancreatic cancer. Cancer Med. 2018, 7, 5036–5046. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Geretti, E.; Klagsbrun, M. Neuropilins. Cell Adhes. Migr. 2007, 1, 56–61. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Czaplicka, A.; Lachota, M.; Pączek, L.; Zagożdżon, R.; Kaleta, B. Chimeric Antigen Receptor T Cell Therapy for Pancreatic Cancer: A Review of Current Evidence. Cells 2024, 13, 101. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- El-Serag, H.B. Hepatocellular carcinoma. N. Engl. J. Med. 2011, 365, 1118–1127. [Google Scholar] [CrossRef] [PubMed]
- Wittmann, P.; Grubinger, M.; Gröger, C.; Huber, H.; Sieghart, W.; Peck-Radosavljevic, M.; Mikulits, W. Neuropilin-2 induced by transforming growth factor-β augments migration of hepatocellular carcinoma cells. BMC Cancer 2015, 15, 909. [Google Scholar] [CrossRef] [PubMed]
- Coulouarn, C.; Corlu, A.; Glaise, D.; Guénon, I.; Thorgeirsson, S.S.; Clément, B. Hepatocyte–Stellate Cell Cross-Talk in the Liver Engenders a Permissive Inflammatory Microenvironment That Drives Progression in Hepatocellular Carcinoma. Cancer Res. 2012, 72, 2533–2542. [Google Scholar] [CrossRef]
- Yan, X.-L.; Fu, C.-J.; Chen, L.; Qin, J.-H.; Zeng, Q.; Yuan, H.-F.; Nan, X.; Chen, H.-X.; Zhou, J.-N.; Lin, Y.-L.; et al. Mesenchymal stem cells from primary breast cancer tissue promote cancer proliferation and enhance mammosphere formation partially via EGF/EGFR/Akt pathway. Breast Cancer Res. Treat. 2012, 132, 153–164. [Google Scholar] [CrossRef]
- Cao, S.; Yaqoob, U.; Das, A.; Shergill, U.; Jagavelu, K.; Huebert, R.C.; Routray, C.; Abdelmoneim, S.; Vasdev, M.; Leof, E.; et al. Neuropilin-1 promotes cirrhosis of the rodent and human liver by enhancing PDGF/TGF-β signaling in hepatic stellate cells. J. Clin. Investig. 2010, 120, 2379–2394. [Google Scholar] [CrossRef] [PubMed]
- Wang, Y.B.; Zheng, K.W.; Hu, Y.Y.; Salameen, H.; Zhu, Z.Y.; Wu, F.F.; Ding, X. VEGF/Nrp1/HIF-1α promotes proliferation of hepatocellular carcinoma through a positive feedback loop. Med. Oncol. 2023, 40, 339. [Google Scholar] [CrossRef]
- Xu, Z.C.; Shen, H.X.; Chen, C.; Ma, L.; Li, W.Z.; Wang, L.; Geng, Z.M. Neuropilin-1 promotes primary liver cancer progression by potentiating the activity of hepatic stellate cells. Oncol. Lett. 2018, 15, 2245–2251. [Google Scholar] [CrossRef]
- Elpek, G.Ö. Neuropilins and liver. World J. Gastroenterol. 2015, 21, 7065–7073. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Ao, J.; Qiang, N.; Kanzaki, H.; Nakamura, M.; Kakiuchi, R.; Zhang, J.; Kojima, R.; Koroki, K.; Inoue, M.; Kanogawa, N.; et al. Dual effects of targeting neuropilin-1 in lenvatinib-resistant hepatocellular carcinoma: Inhibition of tumor growth and angiogenesis. Am. J. Physiol. Physiol. 2024, 327, C1150–C1161. [Google Scholar] [CrossRef]
- Wu, Q.; Pan, C.; Zhou, Y.; Wang, S.; Xie, L.; Zhou, W.; Ding, L.; Chen, T.; Qian, J.; Su, R.; et al. Targeting neuropilin-1 abolishes anti-PD-1-upregulated regulatory T cells and synergizes with 4-1BB agonist for liver cancer treatment. Hepatology 2023, 78, 1402–1417. [Google Scholar] [CrossRef]
- Dong, X.; Guo, W.; Zhang, S.; Wu, T.; Sun, Z.; Yan, S.; Zheng, S. Elevated expression of neuropilin-2 associated with unfavorable prognosis in hepatocellular carcinoma. OncoTargets Ther. 2017, 10, 3827–3833. [Google Scholar] [CrossRef] [PubMed] [PubMed Central]
- Gene Expression Profiling Interactive Analysis. Available online: http://gepia2.cancer-pku.cn/ (accessed on 15 May 2025).
- Tang, Z.; Kang, B.; Li, C.; Chen, T.; Zhang, Z. GEPIA2: An enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 2019, 47, W556–W560. [Google Scholar] [CrossRef] [PubMed]
- Wei, Y.; Guo, S.; Tang, J.; Wen, J.; Wang, H.; Hu, X.; Gu, Q. MicroRNA-19b-3p suppresses gastric cancer development by negatively regulating neuropilin-1. Cancer Cell Int. 2020, 20, 193. [Google Scholar] [CrossRef] [PubMed]
- Li, J.; Liu, L. miR-124-3p inhibits CRC proliferation, migration, and invasion by targeting ITGB1. Discov. Oncol. 2025, 16, 158. [Google Scholar] [CrossRef] [PubMed]
- Zhang, H.; Wang, R.; Wang, M. miR-331-3p suppresses cell invasion and migration in colorectal carcinoma by directly targeting NRP2. Oncol. Lett. 2019, 18, 6501–6508. [Google Scholar] [CrossRef]
- Jin, Y.; Che, X.; Qu, X.; Li, X.; Lu, W.; Wu, J.; Wang, Y.; Hou, K.; Li, C.; Zhang, X.; et al. CircHIPK3 Promotes Metastasis of Gastric Cancer via miR-653-5p/miR-338-3p-NRP1 Axis Under a Long-Term Hypoxic Microenvironment. Front. Oncol. 2020, 10, 1612. [Google Scholar] [CrossRef]
Ligand | NRP-1 | NRP-2 |
---|---|---|
VEGF family proteins | ||
VEGF-A165 | + | + |
VEGF-A121 | + | |
VEGF-B167 | + | |
VEGF-C | + | + |
VEGF-D | + | + |
PlGF-2 | + | + |
VEGFR (R1/R2/R3) | + | + |
Semaphorin family proteins | ||
SEMA3A | + | |
SEMA3B, C, D, F | + | + |
SEMA3G | + | |
Plexin-A1 to A4, D1 | + | + |
Other growth factors | ||
TGF-β1 and LAP | + | + |
TGF-β receptors (TbRI, TbRII) | + | + |
FGF-1, 2, 4, 7 | + | + |
FGFR-1 | + | |
Other molecules | ||
Heparin | + | |
HGF and c-MET | + | + |
PDGF and PDGFR | + | |
Integrins (α5β1, αvβ3) | + | + |
Fibronectin | + |
Neuropilin (NRP) | Cancer Type | Activity | Effect |
---|---|---|---|
NRP-1 | Gastric cancer | Activation of VEGF and TGF-β, regulation of EMT | Increased angiogenesis, invasiveness and metastasis |
Colorectal cancer | Promotion of tumour cell migration via VEGF and PI3K/AKT signalling | Increased aggressiveness and resistance to treatment | |
Pancreatic cancer | Involvement in the activation of tumour-associated fibroblasts (CAFs), regulation of the cancer microenvironment | Increased desmoplasia and cancer progression | |
Liver cancer | Facilitates EMT by promoting the migration of cancer cells and enhancing their metastatic potential | Increased expression, associated with lower patient survival, higher risk of vascular invasion, and activation of HSC | |
NRP-2 | Colorectal cancer | Regulation of VEGF-C/D signalling and lymphangiogenesis | Greater propensity for lymph node metastasis |
Pancreatic cancer | Promotes immunosuppression through effects on Treg cells | Bypassing the immune response and cancer progression | |
Gastric cancer | Supports PI3K/AKT and MAPK pathways | Increased proliferation and resistance to treatment |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Królikowska, K.; Kurman, N.; Błaszczak, K.; Ławicki, S.; Gudowska-Sawczuk, M.; Zajkowska, M. The Significance of Neuropilins in Gastrointestinal Cancers. Int. J. Mol. Sci. 2025, 26, 4937. https://doi.org/10.3390/ijms26104937
Królikowska K, Kurman N, Błaszczak K, Ławicki S, Gudowska-Sawczuk M, Zajkowska M. The Significance of Neuropilins in Gastrointestinal Cancers. International Journal of Molecular Sciences. 2025; 26(10):4937. https://doi.org/10.3390/ijms26104937
Chicago/Turabian StyleKrólikowska, Kinga, Natalia Kurman, Katarzyna Błaszczak, Sławomir Ławicki, Monika Gudowska-Sawczuk, and Monika Zajkowska. 2025. "The Significance of Neuropilins in Gastrointestinal Cancers" International Journal of Molecular Sciences 26, no. 10: 4937. https://doi.org/10.3390/ijms26104937
APA StyleKrólikowska, K., Kurman, N., Błaszczak, K., Ławicki, S., Gudowska-Sawczuk, M., & Zajkowska, M. (2025). The Significance of Neuropilins in Gastrointestinal Cancers. International Journal of Molecular Sciences, 26(10), 4937. https://doi.org/10.3390/ijms26104937