Claudin-18.2 as a therapeutic target in cancers: cumulative findings from basic research and clinical trials

References

• Zihni C, Mills C, Matter K, Balda MS. Tight junctions: from simple barriers to multifunctional molecular gates. Nat Rev Mol Cell Biol. 2016;17(9):64–79. doi:https://doi.org/10.1038/nrm.2016.80.
   Web of Science ®Google Scholar
• Kyuno D, Takasawa A, Kikuchi S, Takemasa I, Osanai M, Kojima T. Role of tight junctions in the epithelial-to-mesenchymal transition of cancer cells. Biochim Biophys Acta Biomembr. 2021;1863(3):183503. doi:https://doi.org/10.1016/j.bbamem.2020.183503.
   PubMed Web of Science ®Google Scholar
• Brunner J, Ragupathy S, Borchard G. Target specific tight junction modulators. Adv Drug Deliv Rev. 2021;171:266–288. doi:https://doi.org/10.1016/j.addr.2021.02.008.
   PubMed Web of Science ®Google Scholar
• Schlingmann B, Molina SA, Koval M. Claudins: gatekeepers of lung epithelial function. Seminars in Cell & Developmental Biology 2015; 42:47–57. doi: https://doi.org/10.1016/j.semcdb.2015.04.009.
   Google Scholar
• Kyuno D, Zhao K, Bauer N, Ryschich E, Zoller M. Therapeutic targeting cancer-initiating cell markers by exosome miRNA: efficacy and functional consequences exemplified for claudin7 and EpCAM. Transl Oncol. 2019;12:191–199. doi:https://doi.org/10.1016/j.tranon.2018.08.021.
   PubMed Web of Science ®Google Scholar
• Sahin U, Koslowski M, Dhaene K, Usener D, Brandenburg G, Seitz G, Huber C, Türeci Ö. Claudin-18 splice variant 2 is a pan-cancer target suitable for therapeutic antibody development. Clin Cancer Res. 2008;14(23):7624–7634. doi:https://doi.org/10.1158/1078-0432.CCR-08-1547.
   PubMed Web of Science ®Google Scholar
• Klempner SJ, Ajani JA, Al-Batran S-E, Bang Y-J, Catenacci DVT, Enzinger PC, Ilson DH, Kim S, Lordick F, Shah MA, et al. Phase II study of zolbetuximab plus pembrolizumab in claudin 18.2: positive locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma (G/GEJ)—ILUSTRO Cohort 3. J Clin Oncol. 2021;39: TPS260–TPS. doi:https://doi.org/10.1200/JCO.2021.39.3_suppl.TPS260.
   Google Scholar
• Yamaguchi K, Shitara K, Al-Batran SE, Bang YJ, Catenacci D, Enzinger P, Ilson D, Kim S, Lordick F, Shah M, et al. SPOTLIGHT: comparison of zolbetuximab or placebo + mFOLFOX6 as first-line treatment in patients with claudin18.2+/HER2– locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma (GEJ): a randomized phase III study. Annals of Oncology. 2019;30:ix66–ix7. doi:https://doi.org/10.1093/annonc/mdz422.074.
   Web of Science ®Google Scholar
• Xu RH, Ajani JA, Al-Batran SE, Bang YJ, Catenacci D, Enzinger PC, Ilson DH, Kim S, Lordick F, Shitara K, et al. 195TiP GLOW: phase III study of first-line zolbetuximab + CAPOX versus placebo + CAPOX in Claudin18.2⁺/HER2⁻ advanced/metastatic gastric or gastroesophageal junction adenocarcinoma (G/GEJ). Annals of Oncology. 2020;31:S1315–S6. doi:https://doi.org/10.1016/j.annonc.2020.10.459.
   Web of Science ®Google Scholar
• Tsukita S, Furuse M, Itoh M. Multifunctional strands in tight junctions. Nat Rev Mol Cell Biol. 2001;2(4):285–293. doi:https://doi.org/10.1038/35067088.
   PubMed Web of Science ®Google Scholar
• Zeisel MB, Dhawan P, Baumert TF. Tight junction proteins in gastrointestinal and liver disease. Gut. 2019;68(3):547–561. doi:https://doi.org/10.1136/gutjnl-2018-316906.
   PubMed Web of Science ®Google Scholar
• Suh Y, Yoon CH, Kim RK, Lim EJ, Oh YS, Hwang SG, An S, Yoon G, Gye MC, Yi J-M, et al. Claudin-1 induces epithelial-mesenchymal transition through activation of the c-Abl-ERK signaling pathway in human liver cells. Oncogene. 2013;32(41):4873–4882. doi:https://doi.org/10.1038/onc.2012.505.
   PubMed Web of Science ®Google Scholar
• Gowrikumar S, Ahmad R, Uppada SB, Washington MK, Shi C, Singh AB, Dhawan P. Upregulated claudin-1 expression promotes colitis-associated cancer by promoting beta-catenin phosphorylation and activation in Notch/p-AKT-dependent manner. Oncogene. 2019;38(26):5321–5337. doi:https://doi.org/10.1038/s41388-019-0795-5.
   PubMed Web of Science ®Google Scholar
• Dhawan P, Ahmad R, Chaturvedi R, Smith JJ, Midha R, Mittal MK, Krishnan M, Chen X, Eschrich S, Yeatman TJ, et al. Claudin-2 expression increases tumorigenicity of colon cancer cells: role of epidermal growth factor receptor activation. Oncogene. 2011;30(29):3234–3247. doi:https://doi.org/10.1038/onc.2011.43.
   PubMed Web of Science ®Google Scholar
• Che J, Yue D, Zhang B, Zhang H, Huo Y, Gao L, Zhen H, Yang Y, Cao B. Claudin-3 inhibits lung squamous cell carcinoma cell epithelial-mesenchymal transition and invasion via suppression of the Wnt/β-catenin signaling pathway. Int J Med Sci. 2018;15(4):339–351. doi:https://doi.org/10.7150/ijms.22927.
   PubMed Web of Science ®Google Scholar
• Jiang L, Yang Y-D, Fu L, Xu W, Liu D, Liang Q, Zhang X, Xu L, Guan X-Y, Wu B, et al. CLDN3 inhibits cancer aggressiveness via Wnt-EMT signaling and is a potential prognostic biomarker for hepatocellular carcinoma. Oncotarget. 2014;5(17):7663–7676. doi:https://doi.org/10.18632/oncotarget.2288.
   PubMedGoogle Scholar
• Günzel D, Yu ASL. Claudins and the modulation of tight junction permeability. Physiol Rev. 2013;93(2):525–569. doi:https://doi.org/10.1152/physrev.00019.2012.
   PubMed Web of Science ®Google Scholar
• Kyuno D, Kojima T, Yamaguchi H, Ito T, Kimura Y, Imamura M, Takasawa A, Murata M, Tanaka S, Hirata K, et al. Protein kinase Calpha inhibitor protects against downregulation of claudin-1 during epithelial-mesenchymal transition of pancreatic cancer. Carcinogenesis. 2013;34(6):1232–1243. doi:https://doi.org/10.1093/carcin/bgt057.
   PubMedGoogle Scholar
• Bhat AA, Uppada S, Achkar IW, Hashem S, Yadav SK, Shanmugakonar M, Al-Naemi HA, Haris M, Uddin S, et al. Tight junction proteins and signaling pathways in cancer and inflammation: a functional crosstalk. Front Physiol. 2018;9:1942. doi:https://doi.org/10.3389/fphys.2018.01942.
   PubMed Web of Science ®Google Scholar
• Bednarz-Misa I, Fortuna P, Diakowska D, Jamrozik N, Krzystek-Korpacka M. Distinct local and systemic molecular signatures in the esophageal and gastric cancers: possible therapy targets and biomarkers for gastric cancer. Int J Mol Sci. 2020;21(12):21. doi:https://doi.org/10.3390/ijms21124509.
   Web of Science ®Google Scholar
• Yang H, Park H, Lee YJ, Choi JY, Kim T, Rajasekaran N, Lee S, Song K, Hong S, Choi J-S, et al. Development of human monoclonal antibody for Claudin-3 overexpressing carcinoma targeting. Biomolecules. 2019;10(1):51. doi:https://doi.org/10.3390/biom10010051.
   Web of Science ®Google Scholar
• Singh AB, Sharma A, Dhawan P. Claudin family of proteins and cancer: an overview. J Oncol. 2010;2010:541957. doi:https://doi.org/10.1155/2010/541957.
   PubMedGoogle Scholar
• Hewitt KJ, Agarwal R, Morin PJ. The claudin gene family: expression in normal and neoplastic tissues. BMC Cancer. 2006;6(1):186. doi:https://doi.org/10.1186/1471-2407-6-186.
   PubMedGoogle Scholar
• Hagen SJ. Non-canonical functions of claudin proteins: beyond the regulation of cell-cell adhesions. Tissue Barriers. 2017;5(2):e1327839. doi:https://doi.org/10.1080/21688370.2017.1327839.
   PubMed Web of Science ®Google Scholar
• Sahin U, Jaeger D, Marme F, Mavratzas A, Krauss J, De Greve J, Vergote I, Tureci O, et al. First-in-human phase I/II dose-escalation study of IMAB027 in patients with recurrent advanced ovarian cancer (OVAR): preliminary data of phase I part. J Clin Oncol. 2015;33:5537. doi:https://doi.org/10.1200/jco.2015.33.15_suppl.5537.
   Google Scholar
• Adra N, Vaughn DJ, Einhorn L, Hanna NH, Rosales M, Arozullah A, Feldman DR, et al. A phase II study assessing the safety and efficacy of ASP1650 in male patients with incurable platinum refractory germ cell tumors. J Clin Oncol. 2020;38: TPS424–TPS. doi:https://doi.org/10.1200/JCO.2020.38.6_suppl.TPS424.
   Google Scholar
• Micke P, Mattsson JS, Edlund K, Lohr M, Jirstrom K, Berglund A, Botling J, Rahnenfuehrer J, Marincevic M, Pontén F, et al. Aberrantly activated claudin 6 and 18.2 as potential therapy targets in non-small-cell lung cancer. Int J Cancer. 2014;135(9):2206–2214. doi:https://doi.org/10.1002/ijc.28857.
   PubMed Web of Science ®Google Scholar
• Türeci Ö, Kreuzberg M, Walter K, Wöll S, Schmitt R, Mitnacht-Kraus R,  Nakajo I, Yamada T, Sahin U, et al. Abstract 882: the anti-claudin 6 antibody, IMAB027, induces antibody-dependent cellular and complement-dependent cytotoxicity in claudin 6-expressing cancer cells. Cancer Res. 2018;78:882. doi:https://doi.org/10.1158/1538-7445.Am2018-882.
   Web of Science ®Google Scholar
• Niimi T, Nagashima K, Ward JM, Minoo P, Zimonjic DB, Popescu NC, Kimura S. Claudin-18, a novel downstream target gene for the T/EBP/NKX2.1 homeodomain transcription factor, encodes lung- and stomach-specific isoforms through alternative splicing. Mol Cell Biol. 2001;21(21):7380–7390. doi:https://doi.org/10.1128/MCB.21.21.7380-7390.2001.
   PubMed Web of Science ®Google Scholar
• Iwaya M, Hayashi H, Nakajima T, Matsuda K, Kinugawa Y, Tobe Y, Tateishi Y, Iwaya Y, Uehara T, Ota H, et al. Colitis-associated colorectal adenocarcinomas frequently express claudin 18 isoform 2: implications for claudin 18.2 monoclonal antibody therapy. Histopathology. 2021;79(2):227–237. doi:https://doi.org/10.1111/his.14358.
   PubMed Web of Science ®Google Scholar
• Hayashi D, Tamura A, Tanaka H, Yamazaki Y, Watanabe S, Suzuki K, Suzuki K, Sentani K, Yasui W, Rakugi H, et al. Deficiency of claudin-18 causes paracellular H+ leakage, up-regulation of interleukin-1beta, and atrophic gastritis in mice. Gastroenterology. 2012;142(2):292–304. doi:https://doi.org/10.1053/j.gastro.2011.10.040.
   PubMed Web of Science ®Google Scholar
• Hagen SJ, Ang LH, Zheng Y, Karahan SN, Wu J, Wang YE, Caron TJ, Gad AP, Muthupalani S, Fox JG, et al. Loss of tight junction protein Claudin 18 promotes progressive neoplasia development in mouse stomach. Gastroenterology. 2018;155(6):1852–1867. doi:https://doi.org/10.1053/j.gastro.2018.08.041.
   PubMed Web of Science ®Google Scholar
• Suzuki K, Sentani K, Tanaka H, Yano T, Suzuki K, Oshima M, Yasui W, Tamura A, Tsukita S. Deficiency of stomach-type Claudin-18 in mice induces gastric tumor formation independent of H pylori infection. Cell Mol Gastroenterol Hepatol. 2019;8(1):119–142. doi:https://doi.org/10.1016/j.jcmgh.2019.03.003.
   PubMed Web of Science ®Google Scholar
• Yano K, Imaeda T, Niimi T. Transcriptional activation of the human claudin-18 gene promoter through two AP-1 motifs in PMA-stimulated MKN45 gastric cancer cells. Am J Physiol Gastrointest Liver Physiol. 2008;294(1):G336–43. doi:https://doi.org/10.1152/ajpgi.00328.2007.
   PubMed Web of Science ®Google Scholar
• Kim SR, Shin K, Park JM, Lee HH, Song KY, Lee SH, Kim B, Kim S-Y, Seo J, Kim J-O, et al. Clinical significance of CLDN18.2 expression in metastatic diffuse-type gastric cancer. J Gastric Cancer. 2020;20(4):408–420. doi:https://doi.org/10.5230/jgc.2020.20.e33.
   PubMed Web of Science ®Google Scholar
• Nakayama I, Shinozaki E, Sakata S, Yamamoto N, Fujisaki J, Muramatsu Y, Hirota T, Takeuchi K, Takahashi S, Yamaguchi K, et al. Enrichment of CLDN18-ARHGAP fusion gene in gastric cancers in young adults. Cancer Sci. 2019;110:1352–1363. doi:https://doi.org/10.1111/cas.13967.
   PubMed Web of Science ®Google Scholar
• Yang H, Hong D, Cho SY, Park YS, Ko WR, Kim JH, Hur H, Lee J, Kim S-J, Kwon SY, et al. RhoGAP domain-containing fusions and PPAPDC1A fusions are recurrent and prognostic in diffuse gastric cancer. Nat Commun. 2018;9(1):4439. doi:https://doi.org/10.1038/s41467-018-06747-4.
   PubMedGoogle Scholar
• Yao F, Kausalya JP, Sia YY, Teo AS, Lee WH, Ong AG,  Zhang Z, Tan JH, Li G, Bertrand D, et al. Recurrent fusion genes in gastric cancer: CLDN18-ARHGAP26 induces loss of epithelial integrity. Cell Rep. 2015;12:272–285. doi:https://doi.org/10.1016/j.celrep.2015.06.020.
   PubMed Web of Science ®Google Scholar
• Tanaka A, Ishikawa S, Ushiku T, Yamazawa S, Katoh H, Hayashi A, Kunita A, Fukayama M. Frequent CLDN18-ARHGAP fusion in highly metastatic diffuse-type gastric cancer with relatively early onset. Oncotarget. 2018;9(50):29336–29350. doi:https://doi.org/10.18632/oncotarget.25464.
   PubMedGoogle Scholar
• Arnold A, Daum S, von Winterfeld M, Berg E, Hummel M, Rau B, Stein U, Treese C. Prognostic impact of Claudin 18.2 in gastric and esophageal adenocarcinomas. Clin Transl Oncol. 2020;22(12):2357–2363. doi:https://doi.org/10.1007/s12094-020-02380-0.
   PubMed Web of Science ®Google Scholar
• Rohde C, Yamaguchi R, Mukhina S, Sahin U, Itoh K, Tureci O. Comparison of Claudin 18.2 expression in primary tumors and lymph node metastases in Japanese patients with gastric adenocarcinoma. Jpn J Clin Oncol. 2019;49(9):870–876. doi:https://doi.org/10.1093/jjco/hyz068.
   PubMed Web of Science ®Google Scholar
• Coati I, Lotz G, Fanelli GN, Brignola S, Lanza C, Cappellesso R, Pellino A, Pucciarelli S, Spolverato G, Guzzardo V, et al. Claudin-18 expression in oesophagogastric adenocarcinomas: a tissue microarray study of 523 molecularly profiled cases. Br J Cancer. 2019;121:257–263. doi:https://doi.org/10.1038/s41416-019-0508-4.
   PubMed Web of Science ®Google Scholar
• Lu Y, Wu T, Sheng Y, Dai Y, Xia B, Xue Y. Correlation between Claudin-18 expression and clinicopathological features and prognosis in patients with gastric cancer. J Gastrointest Oncol. 2020;11(6):1253–1260. doi:https://doi.org/10.21037/jgo-20-463.
   PubMed Web of Science ®Google Scholar
• Dottermusch M, Kruger S, Behrens HM, Halske C, Rocken C. Expression of the potential therapeutic target claudin-18.2 is frequently decreased in gastric cancer: results from a large Caucasian cohort study. Virchows Arch. 2019;475(5):563–571. doi:https://doi.org/10.1007/s00428-019-02624-7.
   PubMed Web of Science ®Google Scholar
• Tureci O, Sahin U, Schulze-Bergkamen H, Zvirbule Z, Lordick F, Koeberle D, Thuss-Patience P, Ettrich T, Arnold D, Bassermann F, et al. A multicentre, phase IIa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study. Ann Oncol. 2019;30:1487–1495. doi:https://doi.org/10.1093/annonc/mdz199.
   PubMed Web of Science ®Google Scholar
• Sanada Y, Oue N, Mitani Y, Yoshida K, Nakayama H, Yasui W. Down-regulation of the claudin-18 gene, identified through serial analysis of gene expression data analysis, in gastric cancer with an intestinal phenotype. J Pathol. 2006;208(5):633–642. doi:https://doi.org/10.1002/path.1922.
   PubMed Web of Science ®Google Scholar
• Oshima T, Shan J, Okugawa T, Chen X, Hori K, Tomita T, Fukui H, Watari J, Miwa H. Down-regulation of claudin-18 is associated with the proliferative and invasive potential of gastric cancer at the invasive front. PLoS One. 2013;8(9):e74757. doi:https://doi.org/10.1371/journal.pone.0074757.
   PubMed Web of Science ®Google Scholar
• Jun KH, Kim JH, Jung JH, Choi HJ, Chin HM. Expression of claudin-7 and loss of claudin-18 correlate with poor prognosis in gastric cancer. Int J Surg. 2014;12:156–162. doi:https://doi.org/10.1016/j.ijsu.2013.11.022.
   PubMed Web of Science ®Google Scholar
• Ungureanu BS, Lungulescu C-V, Pirici D, Turcu-Stiolica A, Gheonea DI, Sacerdotianu VM, Liliac IM, Moraru E, Bende F, Saftoiu A, et al. Clinicopathologic relevance of Claudin 18.2 expression in gastric cancer: a meta-analysis. Front Oncol. 2021;11:643872. doi:https://doi.org/10.3389/fonc.2021.643872.
   PubMed Web of Science ®Google Scholar
• Sahin U, Tureci O, Manikhas G, Lordick F, Rusyn A, Vynnychenko I, Dudov A, Bazin I, Bondarenko I, Melichar B, et al. FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma. Ann Oncol. 2021doi:https://doi.org/10.1016/j.annonc.2021.02.005.
   Google Scholar
• Park W, O’Reilly EM, Furuse J, Kunieda F, Jie F, Kindler HL. Phase II, open-label, randomized study of first-line zolbetuximab plus gemcitabine and nab-paclitaxel (GN) in Claudin 18.2–positive metastatic pancreatic cancer (mPC). J Clin Oncol. 2020;38: TPS4667–TPS. doi:https://doi.org/10.1200/JCO.2020.38.15_suppl.TPS4667.
   Google Scholar
• Bebnowska D, Grywalska E, Niedzwiedzka-Rystwej P, Sosnowska-Pasiarska B, Smok-Kalwat J, Pasiarski M, Góźdź S, Roliński J, Polkowski W. CAR-T cell therapy-an overview of targets in gastric cancer. J Clin Med. 2020;9(6):1894. doi:https://doi.org/10.3390/jcm9061894.
   Web of Science ®Google Scholar
• Jiang H, Shi Z, Wang P, Wang C, Yang L, Du G, Zhang H, Shi B, Jia J, Li Q, et al. Claudin18.2-specific chimeric antigen receptor engineered T cells for the treatment of gastric cancer. J Natl Cancer Inst. 2019;111:409–418. doi:https://doi.org/10.1093/jnci/djy134.
   PubMedGoogle Scholar
• Zhan X, Wang B, Li Z, Li J, Wang H, Chen L, Jiang H, Wu M, Xiao J, Peng X, et al. Phase I trial of Claudin 18.2-specific chimeric antigen receptor T cells for advanced gastric and pancreatic adenocarcinoma. J Clin Oncol. 2019;37(15_suppl):2509. doi:https://doi.org/10.1200/JCO.2019.37.15_suppl.2509.
   Google Scholar
• Woll S, Schlitter AM, Dhaene K, Roller M, Esposito I, Sahin U, Tureci O, et al. Claudin 18.2 is a target for IMAB362 antibody in pancreatic neoplasms. Int J Cancer. 2014;134:731–739. doi:https://doi.org/10.1002/ijc.28400.
   PubMed Web of Science ®Google Scholar
• Karanjawala ZE, Illei PB, Ashfaq R, Infante JR, Murphy K, Pandey A, Schulick R, Winter J, Sharma R, Maitra A, et al. New markers of pancreatic cancer identified through differential gene expression analyses: claudin 18 and annexin A8. Am J Surg Pathol. 2008;32(2):188–196. doi:https://doi.org/10.1097/PAS.0b013e31815701f3.
   PubMed Web of Science ®Google Scholar
• Lee JH, Kim KS, Kim TJ, Hong SP, Song SY, Chung JB, Park SW. Immunohistochemical analysis of claudin expression in pancreatic cystic tumors. Oncol Rep. 2011;25:971–978. doi:https://doi.org/10.3892/or.2011.1132.
   PubMed Web of Science ®Google Scholar
• Soini Y, Takasawa A, Eskelinen M, Juvonen P, Karja V, Hasegawa T, Murata M, Tanaka S, Kojima T, Sawada N. Expression of claudins 7 and 18 in pancreatic ductal adenocarcinoma: association with features of differentiation. J Clin Pathol. 2012;65:431–436. doi:https://doi.org/10.1136/jclinpath-2011-200400.
   PubMed Web of Science ®Google Scholar
• Ito T, Kojima T, Yamaguchi H, Kyuno D, Kimura Y, Imamura M, Takasawa A, Murata M, Tanaka S, Hirata K, et al. Transcriptional regulation of claudin-18 via specific protein kinase C signaling pathways and modification of DNA methylation in human pancreatic cancer cells. J Cell Biochem. 2011;112(7):1761–1772. doi:https://doi.org/10.1002/jcb.23095.
   PubMed Web of Science ®Google Scholar
• Tureci O, Mitnacht-Kraus R, Woll S, Yamada T, Sahin U. Characterization of zolbetuximab in pancreatic cancer models. Oncoimmunology. 2019;8(1):e1523096. doi:https://doi.org/10.1080/2162402X.2018.1523096.
   PubMed Web of Science ®Google Scholar
• Shinozaki A, Shibahara J, Noda N, Tanaka M, Aoki T, Kokudo N, Fukayama M. Claudin-18 in biliary neoplasms. Its significance in the classification of intrahepatic cholangiocarcinoma. Virchows Arch. 2011;459:73–80. doi:https://doi.org/10.1007/s00428-011-1092-z.
   PubMed Web of Science ®Google Scholar
• Keira Y, Takasawa A, Murata M, Nojima M, Takasawa K, Ogino J, Higashiura Y, Sasaki A, Kimura Y, Mizuguchi T. An immunohistochemical marker panel including claudin-18, maspin, and p53 improves diagnostic accuracy of bile duct neoplasms in surgical and presurgical biopsy specimens. Virchows Arch. 2015;466:265–277. doi:https://doi.org/10.1007/s00428-014-1705-4.
   PubMed Web of Science ®Google Scholar
• Tokumitsu T, Sato Y, Yamashita A, Moriguchi-Goto S, Kondo K, Nanashima A, Asada Y. Immunocytochemistry for Claudin-18 and Maspin in biliary brushing cytology increases the accuracy of diagnosing pancreatobiliary malignancies. Cytopathology. 2017;28(2):116–121. doi:https://doi.org/10.1111/cyt.12368.
   PubMed Web of Science ®Google Scholar
• Takasawa K, Takasawa A, Osanai M, Aoyama T, Ono Y, Kono T, Hirohashi Y, Murata M, Sawada N. Claudin-18 coupled with EGFR/ERK signaling contributes to the malignant potentials of bile duct cancer. Cancer Lett. 2017;403:66–73. doi:https://doi.org/10.1016/j.canlet.2017.05.033.
   PubMed Web of Science ®Google Scholar
• Espinoza JA, Riquelme I, Sagredo EA, Rosa L, Garcia P, Bizama C, Apud-Bell M, Leal P, Weber H, Benavente F, et al. Mucin 5B, carbonic anhydrase 9 and claudin 18 are potential theranostic markers of gallbladder carcinoma. Histopathology. 2019;74(4):597–607. doi:https://doi.org/10.1111/his.13797.
   PubMed Web of Science ®Google Scholar
• Ohta H, Chiba S, Ebina M, Furuse M, Nukiwa T. Altered expression of tight junction molecules in alveolar septa in lung injury and fibrosis. Am J Physiol Lung Cell Mol Physiol. 2012;302(2):L193–205. doi:https://doi.org/10.1152/ajplung.00349.2010.
   PubMed Web of Science ®Google Scholar
• Li G, Flodby P, Luo J, Kage H, Sipos A, Gao D, Ji Y, Beard LL, Marconett CN, DeMaio L. Knockout mice reveal key roles for claudin 18 in alveolar barrier properties and fluid homeostasis. Am J Respir Cell Mol Biol. 2014;51:210–222. doi:https://doi.org/10.1165/rcmb.2013-0353OC.
   PubMed Web of Science ®Google Scholar
• LaFemina MJ, Sutherland KM, Bentley T, Gonzales LW, Allen L, Chapin CJ, okkam D, Sweerus KA, Dobbs LG, Ballard PL, et al. Claudin-18 deficiency results in alveolar barrier dysfunction and impaired alveologenesis in mice. Am J Respir Cell Mol Biol. 2014;51:550–558. doi:https://doi.org/10.1165/rcmb.2013-0456OC.
   PubMed Web of Science ®Google Scholar
• Sweerus K, Lachowicz-Scroggins M, Gordon E, LaFemina M, Huang X, Parikh M, Kanegai C, Fahy JV, Frank JA. Claudin-18 deficiency is associated with airway epithelial barrier dysfunction and asthma. J Allergy Clin Immunol. 2017;139:72–81 e1. doi:https://doi.org/10.1016/j.jaci.2016.02.035.
   PubMed Web of Science ®Google Scholar
• Zhou B, Flodby P, Luo J, Castillo DR, Liu Y, Yu FX, McConnell A, Varghese B, Li G, Chimge NO, et al. Claudin-18-mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis. J Clin Invest. 2018;128:970–984. doi:https://doi.org/10.1172/JCI90429.
   PubMed Web of Science ®Google Scholar
• Shimobaba S, Taga S, Akizuki R, Hichino A, Endo S, Matsunaga T, Watanabe R, Yamaguchi M, Yamazaki Y, Sugatani J, et al. Claudin-18 inhibits cell proliferation and motility mediated by inhibition of phosphorylation of PDK1 and Akt in human lung adenocarcinoma A549 cells. Biochim Biophys Acta. 2016;1863(6):1170–1178. doi:https://doi.org/10.1016/j.bbamcr.2016.02.015.
   PubMed Web of Science ®Google Scholar
• Akizuki R, Eguchi H, Endo S, Matsunaga T, Ikari A. ZO-2 suppresses cell migration mediated by a reduction in matrix metalloproteinase 2 in Claudin-18-expressing lung adenocarcinoma A549 cells. Biol Pharm Bull. 2019;42:247–254. doi:https://doi.org/10.1248/bpb.b18-00670.
   PubMed Web of Science ®Google Scholar
• Sahin U, Schuler M, Richly H, Bauer S, Krilova A, Dechow T, Jerling M, Utsch M, Rohde C, Dhaene K, et al. A phase I dose-escalation study of IMAB362 (Zolbetuximab) in patients with advanced gastric and gastro-oesophageal junction cancer. Eur J Cancer. 2018;100:17–26. doi:https://doi.org/10.1016/j.ejca.2018.05.007.
   PubMed Web of Science ®Google Scholar
• Zhang J, Dong R, Shen L. Evaluation and reflection on claudin 18.2 targeting therapy in advanced gastric cancer. Chin J Cancer Res. 2020;32(2):263–270. doi:https://doi.org/10.21147/j.1000-9604.2020.02.13.
   PubMed Web of Science ®Google Scholar
• Singh P, Toom S, Huang Y. Anti-claudin 18.2 antibody as new targeted therapy for advanced gastric cancer. J Hematol Oncol. 2017;10:105. doi:https://doi.org/10.1186/s13045-017-0473-4.
   PubMed Web of Science ®Google Scholar