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Infigratinib, a Selective Fibroblast Growth Factor Receptor Inhibitor, Suppresses Stent-Induced Tissue Hyperplasia in a Rat Esophageal Model

  • Laboratory Investigation
  • Non-Vascular Interventions
  • Published:
CardioVascular and Interventional Radiology Aims and scope Submit manuscript

Abstract

Purpose

Stent-induced tissue hyperplasia remains a challenge for the application of self-expanding metal stents in the management of esophageal stricture. This study aimed to evaluate the efficacy of infigratinib, which is a selective fibroblast growth factor receptor inhibitor, in the prevention of stent-induced tissue hyperplasia in a rat esophageal model.

Methods

Twenty-four male Sprague–Dawley rats underwent esophageal stent placement and were randomized to receive 1 ml of vehicle, 5 mg/kg infigratinib in 1 ml of vehicle, or 10 mg/kg infigratinib in 1 ml of vehicle via naso-gastric tube once daily for 28 days. Follow-up fluoroscopy was performed on postoperative day 28, and the stented esophageal tissues were harvested for histological and immunofluorescence examinations.

Results

All rats survived until euthanasia on postoperative day 28 without procedure-related adverse events. The incidence of stent migration was 12.5%, 12.5% and 25% in the control group, the 5 mg/kg infigratinib group and, the 10 mg/kg infigratinib group, respectively. The percentage of granulation tissue area, the submucosal fibrosis thickness, the number of epithelial layers, the degree of inflammatory cell infiltration, the degree of collagen deposition, the number of fibroblast growth factor receptor 1 (FGFR1)-expressing myofibroblasts, and the number of proliferating myofibroblasts were all significantly lower in both infigratinib groups than in the control group (P < 0.05) but were not significantly different between the two infigratinib groups (P > 0.05).

Conclusions

Infigratinib significantly suppresses stent-induced tissue hyperplasia by inhibiting FGFR1-mediated myofibroblast proliferation and profibrotic activities in a rat esophageal model.

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References

  1. Bakken JC, Wong Kee Song LM, de Groen PC, Baron TH. Use of a fully covered self-expandable metal stent for the treatment of benign esophageal diseases. Gastrointest Endosc. 2010;72(4):712–20.

    Article  PubMed  Google Scholar 

  2. Chan MQ, Balasubramanian G, Modi RM, et al. Changing epidemiology of esophageal stent placement for dysphagia: a decade of trends and the impact of benign indications. Gastrointest Endosc. 2020;92(1):56-64.e57.

    Article  PubMed  Google Scholar 

  3. Felix NS, de Mendonça L, Braga CL, et al. Effects of the FGF receptor-1 inhibitor, infigratinib, with or without sildenafil, in experimental pulmonary arterial hypertension. Br J Pharmacol. 2019;176(23):4462–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Fuccio L, Hassan C, Frazzoni L, Miglio R, Repici A. Clinical outcomes following stent placement in refractory benign esophageal stricture: a systematic review and meta-analysis. Endoscopy. 2016;48(2):141–8.

    PubMed  Google Scholar 

  5. Gkolfakis P, Siersema PD, Tziatzios G, Triantafyllou K, Papanikolaou IS. Biodegradable esophageal stents for the treatment of refractory benign esophageal strictures. Ann Gastroenterol. 2020;33(4):330–7.

    PubMed  PubMed Central  Google Scholar 

  6. Guagnano V, Furet P, Spanka C, et al. Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6- [4-(4-ethyl-piperazin-1-yl)-phenylamin o]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase. J Med Chem. 2011;54(20):7066–83.

    Article  CAS  PubMed  Google Scholar 

  7. Hirdes MM, Siersema PD, van Boeckel PG, Vleggaar FP. Single and sequential biodegradable stent placement for refractory benign esophageal strictures: a prospective follow-up study. Endoscopy. 2012;44(7):649–54.

    Article  CAS  PubMed  Google Scholar 

  8. Imaz-Iglesia I, García-Pérez S, Nachtnebel A, et al. Biodegradable stents for the treatment of refractory or recurrent benign esophageal stenosis. Expert Rev Med Devices. 2016;13(6):583–99.

    Article  CAS  PubMed  Google Scholar 

  9. Inoue Y, King TE Jr, Barker E, Daniloff E, Newman LS. Basic fibroblast growth factor and its receptors in idiopathic pulmonary fibrosis and lymphangioleiomyomatosis. Am J Respir Crit Care Med. 2002;166(5):765–73.

    Article  PubMed  Google Scholar 

  10. Javle M, Lowery M, Shroff RT, et al. Phase II study of BGJ398 in patients With FGFR-altered advanced cholangiocarcinoma. J Clin Oncol. 2018;36(3):276–82.

    Article  CAS  PubMed  Google Scholar 

  11. Jun EJ, Park JH, Tsauo J, et al. EW-7197, an activin-like kinase 5 inhibitor, suppresses granulation tissue after stent placement in rat esophagus. Gastrointest Endosc. 2017;86(1):219–28.

    Article  PubMed  Google Scholar 

  12. Jun EJ, Song HY, Park JH, et al. In Vivo fluorescence microendoscopic monitoring of stent-induced fibroblast cell proliferation in an esophageal mouse model. J Vasc Interv Radiol. 2018;29(12):1756–63.

    Article  PubMed  Google Scholar 

  13. Kang C. Infigratinib: first approval. Drugs. 2021;81(11):1355–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Karakan T, Utku OG, Dorukoz O, et al. Biodegradable stents for caustic esophageal strictures: a new therapeutic approach. Dis Esophagus. 2013;26(3):319–22.

    Article  CAS  PubMed  Google Scholar 

  15. Katoh M. Therapeutics targeting FGF signaling network in human diseases. Trends Pharmacol Sci. 2016;37(12):1081–96.

    Article  CAS  PubMed  Google Scholar 

  16. Kim EY, Shin JH, Jung YY, Shin DH, Song HY. A rat esophageal model to investigate stent-induced tissue hyperplasia. J Vasc Interv Radiol. 2010;21(8):1287–91.

    Article  PubMed  Google Scholar 

  17. Kim EY, Shin JH, Song HY, et al. Suppression of stent-induced tissue hyperplasia in rats by using small interfering RNA to target matrix metalloproteinase-9. Endoscopy. 2014;46(6):507–12.

    Article  PubMed  Google Scholar 

  18. Kochhar R, Samanta J, Basha J, et al. biodegradable stents for caustic esophageal strictures: do they work? Dysphagia. 2017;32(4):575–82.

    Article  PubMed  Google Scholar 

  19. Lawrance IC, Rogler G, Bamias G, et al. Cellular and molecular mediators of intestinal fibrosis. J Crohns Colitis. 2017;11(12):1491–503.

    PubMed  Google Scholar 

  20. Morizumi S, Sato S, Koyama K, et al. Blockade of pan-fibroblast growth factor receptors mediates bidirectional effects in lung fibrosis. Am J Respir Cell Mol Biol. 2020;63(3):317–26.

    Article  CAS  PubMed  Google Scholar 

  21. Nonaka K, Miyazawa M, Ban S, et al. Different healing process of esophageal large mucosal defects by endoscopic mucosal dissection between with and without steroid injection in an animal model. BMC Gastroenterol. 2013;13:72.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Rijcken E, Sachs L, Fuchs T, Spiegel HU, Neumann PA. Growth factors and gastrointestinal anastomotic healing. J Surg Res. 2014;187(1):202–10.

    Article  CAS  PubMed  Google Scholar 

  23. Song HY, Jung HY, Park SI, et al. Covered retrievable expandable nitinol stents in patients with benign esophageal strictures: initial experience. Radiology. 2000;217(2):551–7.

    Article  CAS  PubMed  Google Scholar 

  24. Spaander MC, Baron TH, Siersema PD, et al. Esophageal stenting for benign and malignant disease: European Society of gastrointestinal endoscopy (ESGE) clinical guideline. Endoscopy. 2016;48(10):939–48.

    Article  PubMed  Google Scholar 

  25. Spaander MCW, van der Bogt RD, Baron TH, et al. Esophageal stenting for benign and malignant disease: European society of gastrointestinal endoscopy (ESGE) Guideline - Update 2021. Endoscopy. 2021;53(7):751–62.

    Article  PubMed  Google Scholar 

  26. Sun WL, Zhu YP, Ni XS, et al. Potential involvement of Fgf10/Fgfr2 and androgen receptor (AR) in renal fibrosis in adult male rat offspring subjected to prenatal exposure to di-n-butyl phthalate (DBP). Toxicol Lett. 2018;282:37–42.

    Article  CAS  PubMed  Google Scholar 

  27. Türkyilmaz Z, Sönmez K, Karabulut R, et al. Mitomycin C decreases the rate of stricture formation in caustic esophageal burns in rats. Surgery. 2009;145(2):219–25.

    Article  PubMed  Google Scholar 

  28. Wick G, Grundtman C, Mayerl C, et al. The immunology of fibrosis. Annu Rev Immunol. 2013;31:107–35.

    Article  CAS  PubMed  Google Scholar 

  29. Ye LP, Zheng HH, Mao XL, Zhang Y, Zhou XB, Zhu LH. Complete circular endoscopic resection using submucosal tunnel technique combined with esophageal stent placement for circumferential superficial esophageal lesions. Surg Endosc. 2016;30(3):1078–85.

    Article  PubMed  Google Scholar 

  30. Zhang S, Ye F, Sun L. Use of stent for prevention of esophageal stricture after circumferential endoscopic submucosal dissection. Dig Endosc Off J Jpn Gastroenterol Endosc Soc. 2019;31(Suppl 1):21.

    Google Scholar 

  31. Zhao H, Zhao L, Zhou Z, Wu Y. The roles of connective tissue growth factor in the development of anastomotic esophageal strictures. Arch Med Sci. 2015;11(4):770–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zuo W, He Y, Li W, et al. Landscape of FGF/FGFR Alterations in 12,372 Chinese cancer patients. J Cancer. 2020;11(22):6695–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was funded by the National Natural Science Fund of China (Grant No. 81871468, 82001937, and 82202282).

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Author notes

  1. Yan Fu and He Zhao contributed equally to this work and are co-first authors.

Authors and Affiliations

  1. Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China

    Yan Fu, He Zhao, Jingui Li, Yawei Li, Tao Gong, Ruosu Wang & Xiao Li

  2. Department of Interventional Ultrasound, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China

    Chao An

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  1. Yan Fu
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Correspondence to Xiao Li.

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All animal procedures were performed in compliance with the study protocol approved by the Institutional Animal and Care and Use Committee and were conducted following the Guide for the Care and Use of Laboratory Animals. This article does not contain any studies with human participants performed by any of the authors.

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Fu, Y., Zhao, H., Li, J. et al. Infigratinib, a Selective Fibroblast Growth Factor Receptor Inhibitor, Suppresses Stent-Induced Tissue Hyperplasia in a Rat Esophageal Model. Cardiovasc Intervent Radiol 46, 1267–1275 (2023). https://doi.org/10.1007/s00270-023-03502-1

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