Back to Journals » Journal of Hepatocellular Carcinoma » Volume 11

Review

Expression and Targeted Application of Claudins Family in Hepatobiliary and Pancreatic Diseases

       

Authors Du F, Xie Y, Wu S, Ji M, Dong B, Zhu C

Received 22 June 2024

Accepted for publication 12 September 2024

Published 25 September 2024 Volume 2024:11 Pages 1801—1821

DOI https://doi.org/10.2147/JHC.S483861

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 6

Editor who approved publication: Dr Mohamed Shaker

Download Article [PDF] 


Fangqian Du,1,* Yuwei Xie,1,* Shengze Wu,1 Mengling Ji,2 Bingzi Dong,3 Chengzhan Zhu1

1Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China; 2Department of Surgery, Institute of Biomedical Sciences, Tokushima University, Tokushima, Japan; 3Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Chengzhan Zhu, Department of Hepatobiliary and Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China, Tel +86 0532-82919552, Fax +86 0532-82911885, Email [email protected] Bingzi Dong, Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China, Tel/Fax +86-82911383, Email [email protected]

Abstract: Hepatobiliary and pancreatic diseases are becoming increasingly common worldwide and associated cancers are prone to recurrence and metastasis. For a more accurate treatment, new therapeutic strategies are urgently needed. The claudins (CLDN) family comprises a class of membrane proteins that are the main components of tight junctions, and are essential for forming intercellular barriers and maintaining cellular polarity. In mammals, the claudin family contains at least 27 transmembrane proteins and plays a major role in mediating cell adhesion and paracellular permeability. Multiple claudin proteins are altered in various cancers, including gastric cancer (GC), esophageal cancer (EC), hepatocellular carcinoma (HCC), pancreatic cancer (PC), colorectal cancer (CRC) and breast cancer (BC). An increasing number of studies have shown that claudins are closely associated with the occurrence and development of hepatobiliary and pancreatic diseases. Interestingly, claudin proteins exhibit different effects on cancer progression in different tumor tissues, including tumor suppression and promotion. In addition, various claudin proteins are currently being studied as potential diagnostic and therapeutic targets, including claudin-3, claudin-4, claudin-18.2, etc. In this article, the functional phenotype, molecular mechanism, and targeted application of the claudin family in hepatobiliary and pancreatic diseases are reviewed, with an emphasis on claudin-1, claudin-4, claudin-7 and claudin-18.2, and the current situation and future prospects are proposed.

Keywords: claudins, hepatocellular carcinoma, cholangiocarcinoma, pancreatic cancer, targeted therapy

Introduction

Hepatobiliary pancreas-related diseases are becoming more common in modern societies and the associated tumors are highly malignant. Most patients are at an advanced stage when diagnosed, and the 5-year survival rate is low, which seriously threatens quality of life.1 The main causes of death in patients with hepatobiliary and pancreatic tumors are recurrence and metastasis, and epithelial-mesenchymal transition (EMT) is crucial for the migration and metastasis of cancer cells.2 Specifically, EMT is a process of transformation of epithelial cells into mesenchymal cells, in which epithelial cells lose apical cell polarity, lose adhesion, and acquire the mesenchymal cell phenotype, thus gaining cell migration abilities, which promotes metastasis and drug resistance.3 This process is largely dependent on the breakdown and loss of tight junctions (TJs) between cells.

TJs are intercellular connection device that provides barrier and/or channel functions in the paracellular cleft and facilitates the maintenance of cell polarity.4–7 TJs are composed of four transmembrane proteins, including occludin, tricellulin, marvelD3 and claudins, which belong to TJ-associated marvel protein (TAMP) family.8–12 Claudins are the main components of tight junctions and function in mediating cell adhesion and paracellular permeability.13–17 The claudin family contains at least 27 transmembrane proteins,16,18 and the molecular weight of human claudin proteins range from 21–34 kDa.17 Structurally, claudins are composed of four transmembrane segments, two extracellular segments (ECS) and one intracellular loop (Figure 1).19 Among these structures, the ECS of claudins plays an important role in determining claudin function.20,21

Figure 1 Structure of Claudin protein. (By Figdraw).

Claudin family members not only form pores to regulate extracellular fluid and ions in epithelial cells, but also maintain epithelial homeostasis. Dysregulation of claudin proteins has been identified as an important mechanism for the loss of cell adhesion and metastasis, which leads to structural destruction and impaired function of epithelial and endothelial cells. Dysregulation of claudin expression has been shown to be associated with a variety of human diseases, among which it is most common in tumors, and changes in claudin expression are associated with specific pathogenic events (Table 1). In terms of carcinogenesis, different dysregulated claudin isoforms have different effects on different target cells (Table 2).22–27 In recent years, claudin-18.2 has been increasingly used as a therapeutic target in solid tumors. This article summarizes the role of claudin family of proteins in hepatobiliary and pancreatic tumors and their potential as therapeutic targets.

Table 1 Claudins in Non-Neoplastic Disease

Table 2 Claudins in Neoplastic Disease

Claudin-1

Claudin-1 Benign Disease

Claudin-1 (CLDN1) is the first member of the claudin family and has a molecular weight of 22 kDa.14 It is crucial for epithelial barrier function68 and plays a role in inflammation and tumor progression in various organs.

Claudin-1 is closely associated with hepatitis C and liver cancers and plays a role in the entry of the HCV virus into hepatocytes.69,70 Specifically, the complex formed by claudin-1 and CD81 plays an important role in regulating the entry of HCV virus into cells.71–73 Antibodies targeting claudin-1 can neutralize HCV infectivity by reducing E2 binding to the cell surface and disrupting the CD81-claudin-1 interaction.72 These proteins provide a new targets for the treatment of HCV infection. Compared with common benign hepatobiliary diseases, pancreatic inflammation and other benign diseases have little correlation with claudin-1.

Claudin-1 Malignant Disease

Claudin-1 Functional Phenotype

Claudin-1 is involved in cancer invasion and metastasis and closely relates to hepatobiliary and pancreatic tumors. Furthermore, Claudin-1 is involved in the occurrence and metastasis of HCC,74–76 and claudin-1 also regulates cholangiocarcinoma (CCA) cell invasiveness.77 Simultaneously, the claudin-1 expression level correlates with the prognosis of patients with gallbladder cancer.78,79 Claudin-1 acts as a tumor suppressor in PC in pancreatic cancer.48 Mechanistically, claudin-1 affects tumor progression by regulating epithelial mesenchymal transition (EMT). Claudin-1 overexpression induces EMT by activating the c-Abl/ERK signaling pathway to regulate the expression of the transcription factors Slug and Zeb1, thereby promoting the invasiveness of HCC cells.80 miR-193b expression inhibits pancreatic ductal adenocarcinoma (PDAC) cell proliferation, migration, invasion and EMT by inhibiting the eEF2K/MAPK-ERK oncogenic axis while upregulating the expression of E-cadherin and claudin-1.81 Downregulation of 5-HT1B and 5-HT1D receptors,82 synthetic 8-hydroxydeoxyguanosine (synthetic 8-OHdG),83 or knockdown of LONP184 can inhibit the EMT of pancreatic cancer cells by upregulating claudin-1.

The Claudin-1 Molecular Pathway

Claudin-1 regulates multiple pathways and is involved in cancer progression. The c-Abl-protein kinase Cδ (PKCδ) signaling pathway and the c-Abl/Raf/Ras/ERK signaling pathway function with claudin-1 to enhance HCC invasion.80,85,86 Furthermore, claudin-1 participates in the cell dissociation process of PC cells by activating mitogen-activated protein kinase 2 (MEK2).87 The expression of claudin-1 is regulated by multiple factors. As its upstream molecule, hgH inhibits claudin-1 expression and promotes the stem cell properties of HCC.88 Interestingly, TMPRSS4 promotes tumor sphere formation ability and cancer stem cell (CSC) traits by upregulating claudin-1.89 In addition, mitochondrial defects, heat shock factor 1(HSF1), lactate dehydrogenase B(LDHB), and miR-29a affect the role of claudin-1 in mediating HCC invasiveness.90–92 As a key molecule, claudin-1 is involved in regulating CCA invasiveness by multiple molecules and pathways, such as the P38 MAPK signaling pathway, polypeptide N-acetylgalactosaminotransferase-5 (GALNT5), etc.77,93 Furthermore, claudin-1 expression in human pancreatic cancer cells is induced by tumor necrosis factor--α (TNF-α).94 In pancreatic cancer tissue, ZIP495 as well as the distribution-deficient protein Par3-Tiam1 downregulate the tight junction marker proteins ZO-1 and claudin-1, thereby promoting pancreatic cancer invasion and metastasis.96 PKCα downregulates claudin-1 through Snail and mitogen-activated protein kinase/ERK-dependent pathways.97

Claudin-1-Targeted Applications

Recent research has found that claudin-1 antibodies may provide therapeutic opportunities for HCC.80 Among which, targeting claudin-1 can treat HCC by affecting tumor stemness, metabolism, oncogenic signaling and disrupting the tumor immune microenvironment.80 Currently, Alentis Therapeutics had developed two Claudin-1 monoclonal antibodies, ALE-F02 and ALE-C04.

Claudin-4

Claudin-4 Benign Disease

Claudin-4 (CLDN4) is composed of 209 amino acids, with four transmembrane segments, and is an integral component of tight junctions. Few studies have investigated the role of claudin-4 in benign hepatobiliary and pancreatic diseases. However, a few studies have found that the core genes CDH1 and claudin-4, which may be regulated by FOXP3 or USF2, play important roles in acute pancreatitis (AP).98

Claudin-4 Malignant Disease

Claudin-4 Functional Phenotype

Claudin-4 is differentially expressed in various cancers including HCC and CCA tissues, and can be used as a marker to distinguish HCC from CCA.99,100 A study conducted multiple linear regression analysis of standardized gene expression data for differential expression between CCA and HCC, and used claudin-4 to develop a “CCA diagnostic equation”, which was used to improve the accuracy of CCA diagnosis.101 Compared with hepatobiliary tumors, there are relatively more studies on claudin-4 in pancreatic tumors. Claudin-4 is closely associated with PC occurrence and progression, and different types of pancreatic cancer have different claudin-4 expression levels.102 Claudin-4 can be used to differentiate pancreatic ductal adenocarcinoma (PDAC) from benign epithelium (BE) surrounding tumor tissue.103 Furthermore, the expression of claudin-4 is associated with pancreatic tumor progression, especially with unique pathways of intestinal differentiation.49,104 Claudin-4 can be used as a prognostic marker for liver cancer and pancreatic ductal adenocarcinoma.105

The Claudin-4 Molecular Pathway

Claudin-4, a downstream molecule of zinc finger protein 703 (ZNF703), mediates EMT of HCC.106 In pancreatic cancer tissue, claudin-4, as a downstream molecule, is regulated by a variety of factors and pathways in pancreatic cancer tissues. Claudin-4 is a target of the transforming growth factor beta and Ras/Raf/extracellular signal-regulated kinase pathways.107 Inhibiting MEK-ERK signaling in PC cells has been found to increase the expression of E-cadherin and claudin-4, thereby inhibiting the invasive activity of pancreatic cancer cells.108 During EMT in human PC cells, PKCα activation downregulates TJ barrier function and the clostridium perfringens enterotoxin (CPE) receptor by modifying claudin-1 and claudin-4.109 The transcription factors DEC1 and BACH1 regulate claudin-4 expression in PC, thereby affecting EMT.110,111

Claudin-4 Targeted Application

Currently, many studies have evaluated clinical applications of claudin-4; however, the scope of its application is limited to the pancreas. Residues inside and outside the ECS2 structural domain of the claudin-4 protein are used for subtype-specific targeting by the c-terminal fragment of CPE (C-CPE),112–116 thereby achieving the effects of targeted claudin-4 radiography and cancer therapy. As a target of radiographic imaging, claudin-4 can detect pancreatic cancer and precancerous lesions, which contributes to the early detection of pancreatic cancer.107,117–121 In addition, claudin-4 is also an effective target for cancer therapy.122 Targeting claudin-4 may improve the effectiveness and safety of anticancer drug treatments for pancreatic ductal carcinoma (PDC).123 Interestingly, the effect of CPE targeting claudin-4 in normal HPDE cells differs from that in PC, which may relate to the different localization of claudin-4 in normal HPDE cells and PC cells.124 Based on the spatial structure of claudin-4, a recent study developed a synthetic antibody fragment (sFab) that binds to human claudin-4 ---- COP-1.125 Taken together, claudin-4 may serve as a target for radiological imaging and pancreatic cancer therapy.

Claudin-7

Claudin-7 Benign Disease

Claudin-7 (CLDN7) consists of 211 amino acid residues and is mainly distributed in the intestine, stomach, lungs, bladder, skin and kidneys.126 The expression levels of claudin-7 vary in tumor tissues, and claudin-7 expression in malignant tumor tissues may be relate to tumor grade and prognosis.127–130 Current research on benign hepatobiliary and pancreatic diseases has not found a correlation between claudin-7 and these diseases.

Claudin-7 Malignant Disease

Claudin-7 Functional Phenotype

Compared with normal liver tissue, the expression of claudin-1 and claudin-7 is increased in cirrhosis and hepatocellular carcinoma.76,131 The downregulated or abnormal expression of claudin-7 is associated with liver metastasis of malignant tumors.132 A prior survival analysis showed that patients with high claudin-7 expression in HCC tissues had better prognosis than those without.131 Furthermore, other studies have reported that downregulation of claudin-7 is a positive prognostic marker in HCC.105 Similar to claudin-4, claudin-7 may be a useful marker for distinguishing HCC from CCA in humans,100 and this conclusion has also been verified in canine specimen studies.133 Notably, the expression of claudin-7 has helped distinguish different types of pancreatic tumors,134 and claudin-7 expression has been found to differ in pancreatic adenocarcinoma, with different degrees of differentiation.135 In PC cells, claudin-7 knockdown induces significant proliferation inhibition.136 Furthermore, studies on tumors in PC have found that the TJ protein claudin-7 binds to the tumor marker EpCAM to inhibit EpCAM-mediated cell-cell adhesion and promote migration, proliferation, apoptosis resistance and tumorigenicity.137–139 Claudin-7-dependent tumor exosomes promote non-metastatic tumor cells to restore cancer-initiating cell (CIC) activity.140 It was further proposed that LDN7 can serve as a CIC biomarker,139 however, the prerequisites for claudin-7 as a CIC marker involve glycolipid-rich membrane microdomain (GEM) localization and palmitoylation. In addition, claudin-7 not only affects the assembly of tumor exosomes, but palmitoylated claudin-7 also helps transmit information through exosomes.141

Other Claudins

Other claudin molecules associated with hepatobiliary and pancreatic diseases include claudin-2, 3, 5, 6, 9, 10, 11, 12, 14, 17, and 23 isoforms. Among them, barrier-forming claudin-3, −5, −6, −9, −11, and-14 mainly form tightly closed paracellular barriers, pore-forming claudin −2, −10a/b, and-17 can selectively pass ions and solutes, while the barrier or channel-forming functions of claudins −12, −23 has not yet been determined.17,142–144

Benign Disease

Plasma claudin-3 is a marker of intestinal permeability(IP) in patients with liver disease.145 In the liver, claudin-3 is vital to maintain metabolic homeostasis, retention of bile acids, and optimal hepatocyte proliferation during liver regeneration.146 claudin-2 and claudin-3 relate to cholesterol stones, and in mouse experiments, knockdown of claudin-2 and claudin-3 was found to increase susceptibility to cholesterol gallstone disease.147,148 As mentioned previously, claudin-1 plays a role in HCV entry, and claudin-6 and claudin-9 can also mediate HCV entry into target cells.149

Malignant Disease

Functional Phenotype

Multiple claudin isoforms are involved in the occurrence, invasion, and metastasis of hepatobiliary and pancreatic tumors, and the expression level of claudin-5 relates to HCC prognosis.105,150 Fibrolamellar liver cancer is a subtype of HCC, and claudin-5 is specifically expressed in fibrolamellar liver cancer.151 Claudin-6 is upregulated in HCC tissues and promotes HCC progression.152,153 Claudin-9154 and claudin-17155 are related to the aggressiveness of hepatocytes. Claudin-10 is highly expressed in HCC154 and is functionally involved in HCC invasion.155 Claudin-10 is a molecular marker for poor prognosis after liver resection in patients with HCC.154,156 It is worth noting that claudin-1, claudin-2 and claudin-4 are up-regulated in an HCC cell line with claudin-10 overexpression, which indicates that claudin-10 expression in cancer cells may affect the expression levels of its family members.155 Claudin-14 is a direct target of EZH2-mediated H3K27ME3,157 and in HCC tissues, EZH2-H3K27ME3 overexpression enhances HCC migration and invasion by downregulating the claudin-14 expression.157 Low expression of claudin-14 is an independent prognostic factor for decreased survival rate of patients with HCC.157 Furthermore, reduced claudin-3158 and claudin-14157 expression leads to an increase in Wnt/β-catenin signaling, which is a critical driver of EMT.159 The expression of claudin-3 differs in HCC and CCA,158,160 and claudin-3 in bile-derived external vesicles (EVs) is a useful CCA biomarker.160 In pancreatic diseases, claudin-2 provides a useful molecular marker for precancerous PDAC lesions.161 Furthermore, claudin-3 is highly upregulated in PC,115 and claudin-3 upregulation promotes PC cell migration and invasion.162 Similar to claudin-4 expression, different types of PC have different expression levels of claudin-3, among which claudin-3 is highly expressed in pancreatic endocrine tumors.163 Furthermore, claudin-3 expression closely related to PC differentiation.164 Claudin-5 is present in endothelial cells of normal pancreatic tissue,50 and claudin-5 can be used to distinguish different types of PC.134,165 An immunohistochemical study in dogs found that loss of claudin-5 expression may contribute to carcinogenesis in exocrine pancreatic cells.166 Furthermore, some studies have shown that increased claudin-5 expression is associated with poor prognosis of pancreatic adenocarcinoma, which may relate to increased locomotion and A more aggressive carcinomas spread.50

Molecular Pathway

In liver cancer tissues, claudin-3 can significantly inhibit metastasis by inhibiting the Wnt/β-catenin-EMT axis in HCC cells.158 Claudin-6 silencing significantly inhibits the EGFR/AKT/mTOR signaling pathway in HCC, thereby inhibiting cell proliferation, migration, and invasion.152 Claudin-9167 and claudin-17168 affect the Stat3 signaling pathway through Tyk2, which ultimately enhances the metastatic ability of HCC. Claudin-11, a downstream molecule of miR-99b, mediates the inhibitory effect of miR-99b knockdown on HCC cell metastasis in vitro (Figure 2).169 miR-324-3p targets and downregulates claudin-3 to reduce PC cell migration, invasion, tumor formation, microvessel density, and lymph node metastasis.162 In pancreatic adenocarcinoma (PAAD) tissue, claudin-12 serves as a downstream molecule of LINC00857, which is regulated by the transcription factor ZNF460. The upregulation of claudin-12 expression can facilitate the progression of PAAD.170 As a TJ proteins, claudin-23 is involved in the regulation of PC cell dissociation through changes in gene expression and intracellular localization, thus affecting PC progression. Its expression is possibly correlated with the activation of the MEK signaling pathway during PC cell dissociation.54

Figure 2 Regulatory mechanisms of HCC migration and invasion of different CLDN subtypes. (By Figdraw).

Abbreviations: HCC, hepatocellular carcinoma; EMT, epithelial-mesenchymal transition; LDHB, lactate dehydrogenase B; HSF 1, Heat Shock Factor 1; ZNF703, zinc finger protein 703; EZH2, enhancer of zeste homolog 2; PKCα, protein kinase C-α; ERK, extracellular signal-regulated kinase; Zeb1, zinc finger E-box binding homeobox 1; EGFR, epidermal growth factor receptor; AKT, protein kinase B; mTOR, mechanistic target of rapamycin; Tyk2, tyrosine kinase 2; Stat3, signal transducer and activator of transcription 3; MT1-MMP, maturation of membrane type 1-matrix metalloproteinase; MMP2, matrix metalloproteinase 2.

Targeted Application

A human-rat chimeric IgG1 form of the monoclonal antibody (xi-1A2) may serve as a leading candidate rat monoclonal antibody (mAb) for safe claudin-2-targeted cancer therapy.171 With the in-depth research on claudin-3 and hepatobiliary and pancreatic diseases, it was found that Hizikia fusiforme (EHF) can inhibit the main components of TJ such as claudin-1, claudin-3 and claudin-4, thereby tightening TJs to inhibit cancer cell invasion.172 In addition, the receptor for Clostridium perfringens enterotoxin (CPE) happens to be the same as claudin-3 and claudin-4, which provides a natural material for the targeted application of claudin-3.173 Abion developed ABN501, the world’s first monoclonal antibody targeting Claudin-3, for the treatment of breast and ovarian cancer. Notably, a Phase I/II first human clinical trial has been initiated for claudin-6, to evaluate the safety and initial efficacy of human claudin-6 RNA-encoded T cell binding bisspecific antibody BNT142 RNA-LNP in patients with claudin-6-positive advanced solid tumors (NCT05262530).174

Claudin-18.2

Claudin-18 (CLDN18) is divided into two subtypes, of which claudin-18.1 is highly expressed in lung epithelial type I cells, while claudin-18.2 is specifically expressed in gastric tissue.175,176 In normal gastric tissue, claudin-18.2 is buried in the tight junctions of gastric mucosal cells.175,177 Due to malignant transformation and loss of cell polarity, claudin-18.2 is exposed on the surface of tumor cells, making it accessible to antibodies.178

Claudin-18.2 and Gastric Cancer

Functional Phenotype

Prior studies have found that claudin-18.2 protein levels are down-regulated in gastric cancer cells179–181 and increased in gastric adenocarcinomas.182 Notably, claudin-18 is generally maintained in peritoneally disseminated (PD) gastric cancer,183 where claudin-18.2 positivity is associated with more frequent peritoneal metastasis.184 Experiments in mice found that deletion of claudin-18.2 promoted the progression of gastric cancer.177,185 The reason why claudin-18.2 deletion promotes gastric cancer progression may not only relate to TJ dysfunction, but also inflammation mediated by changes in paracellular permeability.186,187 Claudin-18.2 plays a key role in mediating the adhesion between gastric cancer cells and cancer-associated fibroblasts (CAFs), thereby promoting gastric cancer progression and embolization.188 In addition, the claudin-18-ARHGAP fusion gene was found in gastric cancer tissues, which may relate to the aggressive characteristics of gastric cancer.189,190 The fusion gene can cause RHOA activation in diffuse gastric cancer (DGC) and activation of FAK and YAP signaling.191 In gastric cancer tissues, the positive expression of claudin-18.2 closely relates to the tumor immune microenvironment.181,190,192

Molecular Pathway

The claudin-18 protein is divided into two isoforms. As a downstream target gene, claudin-18 is regulated by the T/EBP/NKX2.1 homology domain transcription factor, thereby selectively splicing and encoding the gastric-specific isoform claudin-18.2.175 Regarding the mechanism by which claudin-18.2 deletion promotes the occurrence and progression of gastric cancer, prior research has found that the claudin-18.2 gene serves as a direct downstream target of miR-1303 and mediates miR-1303 regulation during on the proliferation and invasion of gastric cancer cells.179 At the same time, claudin-18.2 protein regulates multiple signaling pathways, thereby affecting the occurrence and progression of gastric cancer, such as p53 and STAT signaling,177 Notch and Wnt signaling pathways,186 YAP/TAZ signaling,193 etc.

Targeted Application

In view of the specific expression characteristics of claudin-18.2 in gastric cancer tissues, molecular imaging194 and claudin-18.2-targeted therapy have become new options for the diagnosis and treatment of gastric cancer.195–199 According to the search results of the ClinicalTrials.gov database, there are currently more than one hundred clinical trials targeting claudin-18.2. Among these, Zolbetuximab is currently the most widely studied and recognized claudin-18.2-targeted therapy.200,201 Zolbetuximab targets binding to claudin-18.2 on the surface of tumor cells. Under normal conditions, cells are tightly connected structures, and Zolbetuximab is difficult to bind to claudin-18.2; in carcinoma, tumor cells overexpress claudin-18.2 and claudin-18.2 is exposed to the outer side of the basement membrane, which makes it easier for Zolbetuximab to bind to claudin-18.2 and play a role (Figure 3).202 Zolbetuximab combined with the anti-programmed cell death 1 antibody inhibited tumor growth more effectively than either drug alone.203

Figure 3 The principle of Zolbetuximab targeting CLDN18.2+ tumor cells. (By Figdraw).

Furthermore, zolbetuximab combined with CAPOX has been tested as a potential first-line therapy (NCT03653507).204 Several early clinical trials presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting explored other targeted approaches to claudin-18.2 in difficult-to-treat advanced solid tumors, including claudin-18.2-targeting antibody-drug conjugate LM-302 and IBI343, bispecific antibody IBI38 against claudin-18.2/CD3, and chimeric antigen receptor T-cell therapy satricabtagene autoleucel.205 Besides IBI38, bispecific antibodies targeting both HER2 and claudin-18.2 can enhance immune effector function to kill gastric cancer cells that express both antigens.206 A novel tri-specific T-cell engager DR303 has recently emerged for claudin-18.2-positive cancer immunotherapy, which can bind to claudin-18.2, human serum albumin (HSA), and CD3, showing significant tumor suppression effects.207 Satricabtagene autoleucel (satri-cel)/CT041, a self-engineered chimeric antigen receptor (CAR) T cell targeting claudin-18.2, has shown potential for treatment with manageable safety in patients with advanced gastric or gastrointestinal stromal tumors expressing claudin-18.2 (NCT03874897).208 The latest research has found that [177Lu]Lu-labeled anti-claudin-18.2 antibody [177Lu]Lu-TST001 shows the potential for radio immunotherapy in a mouse heterologous transplantation model of gastric cancer, which can serve as a potential new targeted therapeutic drug.209 Claudin-18.2 targeted therapy has achieved better results in gastric cancer, although few studies have investigated such therapies in patients with hepatobiliary and pancreatic diseases.

Claudin-18.2 and Hepatobiliary and Pancreatic Diseases

At present, no link between claudin-18 and benign hepatobiliary and pancreatic diseases has been identified; however, claudin-18 affects their occurrence and development. Compared to gastric cancer, claudin-18.2 has been less studied in hepatobiliary and pancreatic diseases. The expression of claudin-18.2 in normal tissues is limited to gastric epithelium,210,211 but claudin-18.2 is also expressed in a variety of gastrointestinal tumors, including gastric cancer, pancreatic cancer, cholangiocarcinoma, etc.212 Claudin-18 is upregulated in tumor tissues of patients with HCC,213 and in pancreatic cancer, claudin-18 is a marker of early oncogenic processes214 and is commonly expressed in precursor PDAC lesions.161,214,215 In addition, claudin-18.2 is highly expressed in PDAC,52,210,211,216,217 and most PDAC specimens show high claudin-18.2 expression, especially well-differentiated PDAC.217 Membrane-bound claudin-18 is a useful marker for the diagnosis of PC,135 and in pancreatic tissue, the expression of claudin-18 and annexin A8 can be used to differentiate between benign reactive glands and pancreatic invasive ductal adenocarcinoma.218 Claudin-18.2 can also be used to distinguish different subtypes of PDAC,219 as it is specifically expressed in the intestinal-type component of intraductal papillary mucinous carcinoma(IPMC).220 The rate of claudin-18.2 positivity is high in pancreatic neoplasms, and it is worth noting that its expression is not limited to the primary tumor but is also maintained in metastases.52 Therefore, claudin-18 represents a marker for identifying the stomach and pancreatobiliary tract as the primary sites of metastatic adenocarcinoma.221,222 Furthermore, claudin-18 can be used to improve the accuracy of diagnosis of pancreatobiliary malignancies.223 The expression of claudin-18.2 correlates with various clinicopathological characteristics, such as lymph node metastasis, distant metastasis, nerve invasion, stage, and survival rate of patients with PDAC.216,217 Among patients, claudin-18 expression positively associates with more differentiated histology and better prognosis.53,217,224 This may relate to the expression of claudin-18 on cancer cells, which promotes the invasion of PC T lymphocytes and anti-tumor immunity.224 Furthermore, activation of the PKC pathway significantly induces the expression of claudin-18 in normal HPDE cells and PC cells.214,225,226

The expression characteristics of claudin-18.2 make it a new and attractive target for antibody therapy in epithelial tumors (Table 3).178 Claudin-18.2 also provides a target for the treatment of gastric cancer and PC.211 The monoclonal antibody zolbetuximab, which targets claudin-18.2, is used to treat pancreatic ductal adenocarcinoma.210,216,227 For the targeted treatment of human claudin-18.2-positive cancers, prior studies have developed a recombinant antibody hu7v3-Fc based on a humanized VHH. In a mouse xenograft model, the anti-tumor efficacy of hu7v3-Fc was significantly higher than that of the zolbetuximab monoclonal antibody.228 In recent years, claudin-18.2-targeted chimeric antigen receptor (CAR) T cell therapy (CAR-T) has become a hot topic in the treatment of gastric cancer and PC.229,230 In addition, targeting claudin-18.2 can be used as a computerized imaging tracer to assist in disease diagnosis.231

Table 3 Clinical Trials Targeting Claudin-18.2 for the Treatment of Solid Tumors. (Date Source: Classical.clinicaltrials.gov)

Conclusion

According to existing research, multiple claudin proteins are closely associated with hepatobiliary and pancreatic diseases. In liver diseases, the mechanism and impact of claudin-1 are more significant. Claudin-2, −6, −9, −10, and −17 may act as adverse factors in the progression of liver cancer. In contrast, claudin-3, −4, −5, −7, −11, and −14 may be favorable factors for the development and prognosis of liver cancer, and claudins expression is often used to distinguish cholangiocarcinoma from liver cancer. Among these, claudin-499,100 and claudin-7100,133 may serve as valuable markers for distinguishing between HCC and CCA. Compared to hepatobiliary diseases, pancreatic tumors and claudin proteins have been studied extensively. Among these, claudin-1, −4, and −23 have tumor suppressor effects, whereas claudin-2, −3, −5, −7, and −12 may have adversely affects the prognosis of patients with pancreatic tumors. In addition, claudin-3,163 claudin-4,102 claudin-5,134,165 claudin-7,134 claudin-18.2219 can be used to distinguish between different types of pancreatic cancer. Regarding claudins targeting drugs, targeting antibodies for claudin-1, claudin-3, and claudin-6 have been developed and entered into preclinical studies. In hepatobiliary and pancreatic diseases, it has been proposed that claudin-4122 and claudin-7 can be used as new molecular targets for the treatment of pancreatic cancer.136 At present, it is known that claudin-18.2 has a good effect in the targeted therapy of gastric cancer. The prospects of targeted therapy for claudin-18 in PC have also been reported; however, the expression and mechanism of action of claudin-18 in hepatobiliary diseases remain unclear. Therefore, strengthening the research on the mechanism of action of claudin-18 and hepatobiliary and pancreatic tumors will be helpful for providing new plans for targeted therapy and immunotherapy of hepatobiliary and pancreatic tumors and carrying out related clinical trials to improve the precision treatment of such diseases. These approaches have the potential to ultimately improve the prognosis of patients with hepatobiliary and pancreatic tumors.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

The study was supported by Taishan Scholars Program of Shandong Province (grant number 2019010668 and NO. tsqn202312382), Natural Science Foundation of Shandong Province (grant number ZR2021MH171, ZR2023MH243), Shandong Higher Education Young Science and Technology Support Program (grant number 2020KJL005 and 2023KJ224).

Disclosure

The authors report no conflicts of interest in this work.

References

1. Li Q, Xia C, Li H, et al. Disparities in 36 cancers across 185 countries: secondary analysis of global cancer statistics. Front Med. 2024;2024:1.

2. Li W, Ng JM, Wong CC, Ng EKW, Yu J. Molecular alterations of cancer cell and tumour microenvironment in metastatic gastric cancer. Oncogene. 2018;37(36):4903–4920. doi:10.1038/s41388-018-0341-x

3. Tomecka P, Kunachowicz D, Górczyńska J, et al. Factors determining epithelial-mesenchymal transition in cancer progression. Int J Mol Sci. 2024;25(16):8972. doi:10.3390/ijms25168972

4. Balda MS, Whitney JA, Flores C, González S, Cereijido M, Matter K. Functional dissociation of paracellular permeability and transepithelial electrical resistance and disruption of the apical-basolateral intramembrane diffusion barrier by expression of a mutant tight junction membrane protein. J Cell Biol. 1996;134(4):1031–1049. doi:10.1083/jcb.134.4.1031

5. Tsukita S, Furuse M. Pores in the wall: claudins constitute tight junction strands containing aqueous pores. J Cell Biol. 2000;149(1):13–16. doi:10.1083/jcb.149.1.13

6. 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):564–580. doi:10.1038/nrm.2016.80

7. Balda MS, Matter K. Tight junctions. Curr Biol. 2023;33(21):R1135–r1140. doi:10.1016/j.cub.2023.09.027

8. Furuse M, Hirase T, Itoh M, et al. Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol. 1993;123(6):1777–1788. doi:10.1083/jcb.123.6.1777

9. McCarthy KM, Skare IB, Stankewich MC, et al. Occludin is a functional component of the tight junction. J Cell Sci. 1996;109(Pt 9):2287–2298. doi:10.1242/jcs.109.9.2287

10. Rajasekaran AK, Hojo M, Huima T, Rodriguez-Boulan E. Catenins and zonula occludens-1 form a complex during early stages in the assembly of tight junctions. J Cell Biol. 1996;132(3):451–463. doi:10.1083/jcb.132.3.451

11. Furuse M, Sasaki H, Fujimoto K, Tsukita S. A single gene product, claudin-1 or −2, reconstitutes tight junction strands and recruits occludin in fibroblasts. J Cell Biol. 1998;143(2):391–401. doi:10.1083/jcb.143.2.391

12. Ikenouchi J, Furuse M, Furuse K, Sasaki H, Tsukita S, Tsukita S. Tricellulin constitutes a novel barrier at tricellular contacts of epithelial cells. J Cell Biol. 2005;171(6):939–945. doi:10.1083/jcb.200510043

13. Furuse M, Fujita K, Hiiragi T, Fujimoto K, Tsukita S. Claudin-1 and −2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J Cell Biol. 1998;141(7):1539–1550. doi:10.1083/jcb.141.7.1539

14. Morita K, Furuse M, Fujimoto K, Tsukita S. Claudin multigene family encoding four-transmembrane domain protein components of tight junction strands. Proc Natl Acad Sci USA. 1999;96(2):511–516. doi:10.1073/pnas.96.2.511

15. Colegio OR, Van Itallie CM, McCrea HJ, Rahner C, Anderson JM. Claudins create charge-selective channels in the paracellular pathway between epithelial cells. Am J Physiol Cell Physiol. 2002;283(1):C142–147. doi:10.1152/ajpcell.00038.2002

16. Mineta K, Yamamoto Y, Yamazaki Y, et al. Predicted expansion of the claudin multigene family. FEBS Lett. 2011;585(4):606–612. doi:10.1016/j.febslet.2011.01.028

17. Günzel D, Yu AS. Claudins and the modulation of tight junction permeability. Physiol Rev. 2013;93(2):525–569. doi:10.1152/physrev.00019.2012

18. Ding L, Lu Z, Lu Q, Chen YH. The claudin family of proteins in human malignancy: a clinical perspective. Cancer Manage Res. 2013;5:367–375. doi:10.2147/CMAR.S38294

19. Vecchio AJ, Rathnayake SS, Stroud RM. Structural basis for Clostridium perfringens enterotoxin targeting of claudins at tight junctions in mammalian gut. Proc Natl Acad Sci USA. 2021;118:15.

20. Krause G, Winkler L, Piehl C, Blasig I, Piontek J, Müller SL. Structure and function of extracellular claudin domains. Ann. N.Y. Acad. Sci. 2009;1165:34–43. doi:10.1111/j.1749-6632.2009.04057.x

21. Krause G, Protze J, Piontek J. Assembly and function of claudins: structure-function relationships based on homology models and crystal structures. Semin Cell Dev Biol. 2015;42:3–12. doi:10.1016/j.semcdb.2015.04.010

22. Soini Y. Expression of claudins 1, 2, 3, 4, 5 and 7 in various types of tumours. Histopathology. 2005;46(5):551–560. doi:10.1111/j.1365-2559.2005.02127.x

23. Osanai M, Murata M, Chiba H, Kojima T, Sawada N. Epigenetic silencing of claudin-6 promotes Anchorage-independent growth of breast carcinoma cells. Can Sci. 2007;98(10):1557–1562. doi:10.1111/j.1349-7006.2007.00569.x

24. Singh AB, Sharma A, Dhawan P. Claudin family of proteins and cancer: an overview. J Oncol. 2010;2010:541957. doi:10.1155/2010/541957

25. Kwon MJ. Emerging roles of claudins in human cancer. Int J Mol Sci. 2013;14(9):18148–18180.

26. Osanai M, Takasawa A, Murata M, Sawada N. Claudins in cancer: bench to bedside. Pflugers Archiv. 2017;469(1):55–67. doi:10.1007/s00424-016-1877-7

27. Ouban A, Arabi TZ. Expression of claudins in preneoplastic conditions of the gastrointestinal tract: a review. Cancers. 2023;15(16). doi:10.3390/cancers15164095

28. Manole E, Ceafalan LC, Oproiu AM, Popa-Wagner A, Popescu BO. Claudin-1 and occludin expression in demyelinating peripheral neuropathies. Rom J Morphol Embryol. 2015;56(3):1097–1102.

29. He L, Yuan SZ, Mao XD, et al. Claudin-10 decrease in the submandibular gland contributes to xerostomia. J Dent Res. 2024;103(2):167–176. doi:10.1177/00220345231210547

30. Hassanzadeh G, Hosseini Quchani S, Sahraian MA, et al. Leukocyte gene expression and plasma concentration in multiple sclerosis: alteration of transforming growth factor-βs, claudin-11, and matrix metalloproteinase-2. Cell Mol Neurobiol. 2016;36(6):865–872. doi:10.1007/s10571-015-0270-y

31. Lee JS, Park HS, Yoon HS, Cho S. Claudin-1 expression decreases with increasing pathological grade in actinic keratosis and may be a marker of high-risk actinic keratosis. Clin Exp Dermatol. 2019;44(5):483–490. doi:10.1111/ced.13810

32. Kuwatsuka S, Koike Y, Kuwatsuka Y, Yamaoka T, Murota H. Claudin-7 in keratinocytes is downregulated by the inhibition of HMG-CoA reductase and is highly expressed in the stratum granulosum of the psoriatic epidermis. J Dermatological Sci. 2021;104(2):132–137. doi:10.1016/j.jdermsci.2021.10.002

33. Yamaga K, Murota H, Tamura A, et al. Claudin-3 loss causes leakage of sweat from the sweat gland to contribute to the pathogenesis of atopic dermatitis. J Invest Dermat. 2018;138(6):1279–1287. doi:10.1016/j.jid.2017.11.040

34. Sweerus K, Lachowicz-Scroggins M, Gordon E, et al. Claudin-18 deficiency is associated with airway epithelial barrier dysfunction and asthma. J Allergy Clin Immunol. 2017;139(1):72–81.e71. doi:10.1016/j.jaci.2016.02.035

35. Puthanmadhom Narayanan S, O’Brien DR, Sharma M, et al. Duodenal mucosal barrier in functional dyspepsia. Clin Gastroenterol Hepatol. 2022;20(5):1019–1028.e1013. doi:10.1016/j.cgh.2021.09.029

36. Songtao Y, Fangyu L, Jie C, Li Y. Identification of claudin-2 as a promising biomarker for early diagnosis of pre-diabetes. Front Pharmacol. 2024;15:1370708. doi:10.3389/fphar.2024.1370708

37. Fink C, Weigel R, Fink L, et al. Claudin-11 is over-expressed and dislocated from the blood-testis barrier in Sertoli cells associated with testicular intraepithelial neoplasia in men. Histochem Cell Biol. 2009;131(6):755–764. doi:10.1007/s00418-009-0576-2

38. Karnati HK, Panigrahi M, Shaik NA, et al. Down regulated expression of Claudin-1 and Claudin-5 and up regulation of β-catenin: association with human glioma progression. CNS Neurolog Disord Drug Targ. 2014;13(8):1413–1426. doi:10.2174/1871527313666141023121550

39. Sun Z, Yan T, Jiang H, Cai J, Zhu X, Chen Q. Claudin-3 facilitates the progression and mediates the tumorigenic effects of TGF-β in glioblastoma multiforme. Med Oncol. 2023;40(9):268. doi:10.1007/s12032-023-02136-0

40. Yang F, Xu W, Tang X, Li Q, Hou X, Hui X. Claudin 4 enhances the malignancy of glioma cells via NNAT/Wnt signaling. Am J Can Res. 2023;13(6):2530–2539.

41. Miskad UA, Aswidah A, Dahlan H, et al. The role of claudin-1 expression in follicular and papillary thyroid neoplasm. Asian Pacif J Can Prev. 2022;23(12):4023–4027. doi:10.31557/APJCP.2022.23.12.4023

42. Nacir M, Ibiloğlu I, Alabalık U. Investigation of ZIP4, ZO-1, and CLAUDIN-1 expression in thyroid tumours by immunohistochemistry and real-time polymerase chain reaction methods. Polish J Pathol. 2023;74(4):248–255. doi:10.5114/pjp.2023.134318

43. Zhang C, Guo C, Li Y, Liu K, Zhao Q, Ouyang L. Identification of claudin-6 as a molecular biomarker in pan-cancer through multiple omics integrative analysis. Front Cell Develop Biol. 2021;9:726656. doi:10.3389/fcell.2021.726656

44. Zhou Y, Xiang J, Bhandari A, et al. CLDN10 is associated with papillary thyroid cancer progression. J Cancer. 2018;9(24):4712–4717. doi:10.7150/jca.28636

45. Chao YC, Pan SH, Yang SC, et al. Claudin-1 is a metastasis suppressor and correlates with clinical outcome in lung adenocarcinoma. Am J Respir Crit Care Med. 2009;179(2):123–133. doi:10.1164/rccm.200803-456OC

46. Ikari A, Watanabe R, Sato T, et al. Nuclear distribution of claudin-2 increases cell proliferation in human lung adenocarcinoma cells. BBA. 2014;1843(9):2079–2088. doi:10.1016/j.bbamcr.2014.05.017

47. Zhang L, Wang Y, Zhang B, et al. Claudin-3 expression increases the malignant potential of lung adenocarcinoma cells: role of epidermal growth factor receptor activation. Oncotarget. 2017;8(14):23033–23047. doi:10.18632/oncotarget.14974

48. Zhu L, Tang N, Hang H, et al. Loss of Claudin-1 incurred by DNMT aberration promotes pancreatic cancer progression. Cancer Lett. 2024;586:216611. doi:10.1016/j.canlet.2024.216611

49. Tsutsumi K, Sato N, Cui L, et al. Expression of claudin-4 (CLDN4) mRNA in intraductal papillary mucinous neoplasms of the pancreas. Mod Pathol. 2011;24(4):533–541. doi:10.1038/modpathol.2010.218

50. Soini Y, Eskelinen M, Juvonen P, et al. Strong claudin 5 expression is a poor prognostic sign in pancreatic adenocarcinoma. Tum Biol. 2014;35(4):3803–3808. doi:10.1007/s13277-013-1503-7

51. Alikanoglu AS, Gunduz S, Demirpence O, et al. Expression pattern and prognostic significance of claudin 1, 4 and 7 in pancreatic cancer. Asian Pacif J Can Prev. 2015;16(10):4387–4392. doi:10.7314/APJCP.2015.16.10.4387

52. Wöll S, Schlitter AM, Dhaene K, et al. Claudin 18.2 is a target for IMAB362 antibody in pancreatic neoplasms. Internat J Can. 2014;134(3):731–739. doi:10.1002/ijc.28400

53. Kayikcioglu E, Yüceer RO. The role of claudin 18.2 and HER-2 in pancreatic cancer outcomes. Medicine. 2023;102(6):e32882. doi:10.1097/MD.0000000000032882

54. Wang W, Tan X, Zhou L, Gao F, Dai X. Involvement of the expression and redistribution of claudin-23 in pancreatic cancer cell dissociation. Molec Med Rep. 2010;3(5):845–850. doi:10.3892/mmr.2010.334

55. Kind S, Büscheck F, Höflmayer D, et al. Claudin-1 upregulation is associated with favorable tumor features and a reduced risk for biochemical recurrence in ERG-positive prostate cancer. World j Urol. 2020;38(9):2185–2196. doi:10.1007/s00345-019-03017-w

56. Orea MJ, Angulo JC, González-Corpas A, et al. Claudin-3 loss of expression is a prognostic marker in castration-resistant prostate cancer. Int J Mol Sci. 2023;24(1):803. doi:10.3390/ijms24010803

57. Radi DA, Abd-Elazeem MA. Prognostic significance of lymphatic vessel density detected by D2-40 and its relation to claudin-4 expression in prostatic adenocarcinoma. Internat J Surg Pathol. 2016;24(3):219–226. doi:10.1177/1066896915611488

58. Ashikari D, Takayama KI, Obinata D, Takahashi S, Inoue S. CLDN8, an androgen-regulated gene, promotes prostate cancer cell proliferation and migration. Can Sci. 2017;108(7):1386–1393. doi:10.1111/cas.13269

59. Kumar B, Ahmad R, Giannico GA, et al. Claudin-2 inhibits renal clear cell carcinoma progression by inhibiting YAP-activation. J Experim Clin Can Res. 2021;40(1):77. doi:10.1186/s13046-021-01870-5

60. Choi YD, Kim KS, Ryu S, et al. Claudin-7 is highly expressed in chromophobe renal cell carcinoma and renal oncocytoma. J Korean Med Sci. 2007;22(2):305–310. doi:10.3346/jkms.2007.22.2.305

61. Ji HC, Li JD, Zhang GL, et al. Significance and possible biological mechanism for CLDN8 downregulation in kidney renal clear cell carcinoma tissues. World J Oncol. 2024;15(4):662–674. doi:10.14740/wjon1869

62. Yang W, Zhang K, Zhang Z, et al. Claudin-10 overexpression suppresses human clear cell renal cell carcinoma growth and metastasis by regulating ATP5O and causing mitochondrial dysfunction. Int J Bio Sci. 2022;18(6):2329–2344. doi:10.7150/ijbs.70105

63. Yang W, Li L, Zhang K, et al. CLDN10 associated with immune infiltration is a novel prognostic biomarker for clear cell renal cell carcinoma. Epigenomics. 2021;13(1):31–45. doi:10.2217/epi-2020-0256

64. Elsayed AM, Mahmoud EI, Salem MM, Khairy RA. Immunohistochemical expression of claudin-1 and claudin-4 in urothelial carcinoma of the urinary bladder. Asian Pacif J Can Prev. 2024;25(2):637–646. doi:10.31557/APJCP.2024.25.2.637

65. Awsare NS, Martin TA, Haynes MD, Matthews PN, Jiang WG. Claudin-11 decreases the invasiveness of bladder cancer cells. Oncol Rep. 2011;25(6):1503–1509. doi:10.3892/or.2011.1244

66. Zhang X, Wang X, Wang A, Li Q, Zhou M, Li T. CLDN10 promotes a malignant phenotype of osteosarcoma cells via JAK1/Stat1 signaling. J Cell Commun Signal. 2019;13(3):395–405. doi:10.1007/s12079-019-00509-7

67. Tian X, He Y, Han Z, Su H, Chu C. The cytoplasmic expression of CLDN12 predicts an unfavorable prognosis and promotes proliferation and migration of osteosarcoma. Cancer Manage Res. 2019;11:9339–9351. doi:10.2147/CMAR.S229441

68. Furuse M, Hata M, Furuse K, et al. Claudin-based tight junctions are crucial for the mammalian epidermal barrier: a lesson from claudin-1-deficient mice. J Cell Biol. 2002;156(6):1099–1111. doi:10.1083/jcb.200110122

69. Evans MJ, von Hahn T, Tscherne DM, et al. Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry. Nature. 2007;446(7137):801–805. doi:10.1038/nature05654

70. Reynolds GM, Harris HJ, Jennings A, et al. Hepatitis C virus receptor expression in normal and diseased liver tissue. Hepatology. 2008;47(2):418–427. doi:10.1002/hep.22028

71. Harris HJ, Farquhar MJ, Mee CJ, et al. CD81 and claudin 1 coreceptor association: role in hepatitis C virus entry. J Virol. 2008;82(10):5007–5020. doi:10.1128/JVI.02286-07

72. Krieger SE, Zeisel MB, Davis C, et al. Inhibition of hepatitis C virus infection by anti-claudin-1 antibodies is mediated by neutralization of E2-CD81-claudin-1 associations. Hepatology. 2010;51(4):1144–1157. doi:10.1002/hep.23445

73. Harris HJ, Davis C, Mullins JG, et al. Claudin association with CD81 defines hepatitis C virus entry. J Biol Chem. 2010;285(27):21092–21102. doi:10.1074/jbc.M110.104836

74. Higashi Y, Suzuki S, Sakaguchi T, et al. Loss of claudin-1 expression correlates with malignancy of hepatocellular carcinoma. J Surg Res. 2007;139(1):68–76. doi:10.1016/j.jss.2006.08.038

75. Holczbauer Á, Gyöngyösi B, Lotz G, et al. Distinct claudin expression profiles of hepatocellular carcinoma and metastatic colorectal and pancreatic carcinomas. J Histoch Cytoch. 2013;61(4):294–305. doi:10.1369/0022155413479123

76. Holczbauer Á, Gyöngyösi B, Lotz G, et al. Increased expression of claudin-1 and claudin-7 in liver cirrhosis and hepatocellular carcinoma. Pathol Oncol Res. 2014;20(3):493–502. doi:10.1007/s12253-013-9683-4

77. Pearngam P, Kumkate S, Okada S, Janvilisri T. Andrographolide inhibits cholangiocarcinoma cell migration by down-regulation of claudin-1 via the p-38 signaling pathway. Front Pharmacol. 2019;10:827. doi:10.3389/fphar.2019.00827

78. Xiong L, Wen Y, Miao X, Yang Z. Expressions of cell junction regulatory proteins and their association with clinicopathologic parameters in benign and malignant gallbladder lesions. Am J Med Sci. 2011;342(5):388–394. doi:10.1097/MAJ.0b013e31821e12af

79. Pyo JS, Kim NY, Cho WJ. Prognostic Role of Claudin-1 Immunohistochemistry in Malignant Solid Tumors: a Meta-Analysis. J Pathol Translat Med. 2019;53(3):173–179. doi:10.4132/jptm.2019.02.03

80. Suh Y, Yoon CH, Kim RK, 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:10.1038/onc.2012.505

81. Gurbuz N, Kahraman N, Sonmez HE, Mokhlis HA, Kosar PA, Ozpolat B. miRNA-193b-5p Suppresses Pancreatic Cancer Cell Proliferation, Invasion, Epithelial Mesenchymal Transition, and Tumor Growth by Inhibiting eEF2K. Anti Can Agent Med Chem. 2022;22(14):2607–2618. doi:10.2174/1871520622666220117123213

82. Gurbuz N, Ashour AA, Alpay SN, Ozpolat B. Down-regulation of 5-HT1B and 5-HT1D receptors inhibits proliferation, clonogenicity and invasion of human pancreatic cancer cells. PLoS One. 2014;9(9):e110067. doi:10.1371/journal.pone.0105245

83. Park JM, Han YM, Jeong M, et al. Synthetic 8-hydroxydeoxyguanosine inhibited metastasis of pancreatic cancer through concerted inhibitions of ERM and Rho-GTPase. Free Radic Biol Med. 2017;110:151–161. doi:10.1016/j.freeradbiomed.2017.06.003

84. Liu C, Wang H, Li H, et al. Inhibition of LONP1 suppresses pancreatic cancer progression via C-jun N-terminal kinase pathway-meditated epithelial-mesenchymal transition. Pancreas. 2019;48(5):629–635. doi:10.1097/MPA.0000000000001321

85. Yoon CH, Kim MJ, Park MJ, et al. Claudin-1 acts through c-Abl-protein kinase Cdelta (PKCdelta) signaling and has a causal role in the acquisition of invasive capacity in human liver cells. J Biol Chem. 2010;285(1):226–233. doi:10.1074/jbc.M109.054189

86. Stebbing J, Filipović A, Giamas G. Claudin-1 as a promoter of EMT in hepatocellular carcinoma. Oncogene. 2013;32(41):4871–4872. doi:10.1038/onc.2012.591

87. Tan X, Egami H, Ishikawa S, et al. Arrangement of expression and distribution of tight junction protein claudin-1 in cell dissociation of pancreatic cancer cells. Int j Oncol. 2004;25(6):1567–1574.

88. Chen YJ, You ML, Chong QY, et al. Autocrine human growth hormone promotes invasive and cancer stem cell-like behavior of hepatocellular carcinoma cells by STAT3 dependent inhibition of CLAUDIN-1 expression. Int J Mol Sci. 2017;18(6):1.

89. Mahati S, Bolati D, Yang Y, Mao R, Zhang H, Bao Y. TMPRSS4 promotes cancer stem cell traits by regulating CLDN1 in hepatocellular carcinoma. Biochem Biophys Res Commun. 2017;490(3):906–912. doi:10.1016/j.bbrc.2017.06.139

90. Kim JH, Kim EL, Lee YK, et al. Decreased lactate dehydrogenase B expression enhances claudin 1-mediated hepatoma cell invasiveness via mitochondrial defects. Exp. Cell. Res. 2011;317(8):1108–1118. doi:10.1016/j.yexcr.2011.02.011

91. Lee JH, Lee YK, Lim JJ, et al. Mitochondrial respiratory dysfunction induces claudin-1 expression via reactive oxygen species-mediated heat shock factor 1 activation, leading to hepatoma cell invasiveness. J Biol Chem. 2015;290(35):21421–21431. doi:10.1074/jbc.M115.654913

92. Mahati S, Xiao L, Yang Y, Mao R, Bao Y. miR-29a suppresses growth and migration of hepatocellular carcinoma by regulating CLDN1. Biochem Biophys Res Commun. 2017;486(3):732–737. doi:10.1016/j.bbrc.2017.03.110

93. Detarya M, Sawanyawisuth K, Aphivatanasiri C, et al. The O-GalNAcylating enzyme GALNT5 mediates carcinogenesis and progression of cholangiocarcinoma via activation of AKT/ERK signaling. Glycobiology. 2020;30(5):312–324. doi:10.1093/glycob/cwz098

94. Kondo J, Sato F, Kusumi T, et al. Claudin-1 expression is induced by tumor necrosis factor-alpha in human pancreatic cancer cells. IntJ Mol Med. 2008;22(5):645–649.

95. Liu M, Yang J, Zhang Y, et al. ZIP4 promotes pancreatic cancer progression by repressing ZO-1 and claudin-1 through a ZEB1-dependent transcriptional mechanism. Clinical Can Res. 2018;24(13):3186–3196. doi:10.1158/1078-0432.CCR-18-0263

96. Guo X, Wang M, Zhao Y, et al. Par3 regulates invasion of pancreatic cancer cells via interaction with Tiam1. Clin Exp Med. 2016;16(3):357–365. doi:10.1007/s10238-015-0365-2

97. Kyuno D, Kojima T, Yamaguchi H, et al. Protein kinase Cα inhibitor protects against downregulation of claudin-1 during epithelial-mesenchymal transition of pancreatic cancer. Carcinogenesis. 2013;34(6):1232–1243. doi:10.1093/carcin/bgt057

98. Ji R, Chen Y, Chen W, et al. Identification of significant genes and pathways in acute pancreatitis via bioinformatical analysis. Dig Dis Sci. 2021;66(9):3045–3053. doi:10.1007/s10620-020-06598-4

99. Lódi C, Szabó E, Holczbauer A, et al. Claudin-4 differentiates biliary tract cancers from hepatocellular carcinomas. Mod Pathol. 2006;19(3):460–469. doi:10.1038/modpathol.3800549

100. Ono Y, Hiratsuka Y, Murata M, et al. Claudins-4 and −7 might be valuable markers to distinguish hepatocellular carcinoma from cholangiocarcinoma. Virchows Archiv. 2016;469(4):417–426. doi:10.1007/s00428-016-1984-z

101. Kraiklang R, Pairojkul C, Khuntikeo N, Imtawil K, Wongkham S, Wongkham C. A novel predictive equation for potential diagnosis of cholangiocarcinoma. PLoS One. 2014;9(2):e89337. doi:10.1371/journal.pone.0089337

102. Tsukahara M, Nagai H, Kamiakito T, et al. Distinct expression patterns of claudin-1 and claudin-4 in intraductal papillary-mucinous tumors of the pancreas. Pathol Internat. 2005;55(2):63–69. doi:10.1111/j.1440-1827.2005.01793.x

103. Furuhata A, Minamiguchi S, Shirahase H, et al. Immunohistochemical antibody panel for the differential diagnosis of pancreatic ductal carcinoma from gastrointestinal contamination and benign pancreatic duct epithelium in endoscopic ultrasound-guided fine-needle aspiration. Pancreas. 2017;46(4):531–538. doi:10.1097/MPA.0000000000000774

104. Foss CA, Fox JJ, Feldmann G, et al. Radiolabeled anti-claudin 4 and anti-prostate stem cell antigen: initial imaging in experimental models of pancreatic cancer. Molec Imag. 2007;6(2):131–139. doi:10.2310/7290.2007.00010

105. Bouchagier KA, Assimakopoulos SF, Karavias DD, et al. Expression of claudins-1, −4, −5, −7 and occludin in hepatocellular carcinoma and their relation with classic clinicopathological features and patients’ survival. Vivo Athens Greece. 2014;28(3):315–326.

106. Wang H, Xu H, Ma F, et al. Zinc finger protein 703 induces EMT and sorafenib resistance in hepatocellular carcinoma by transactivating CLDN4 expression. Cell Death Dis. 2020;11(4):225. doi:10.1038/s41419-020-2422-3

107. Michl P, Barth C, Buchholz M, et al. Claudin-4 expression decreases invasiveness and metastatic potential of pancreatic cancer. Cancer Res. 2003;63(19):6265–6271.

108. Kumei S, Motomura W, Yoshizaki T, Takakusaki K, Okumura T. Troglitazone increases expression of E-cadherin and claudin 4 in human pancreatic cancer cells. Biochem Biophys Res Commun. 2009;380(3):614–619. doi:10.1016/j.bbrc.2009.01.134

109. Kyuno D, Kojima T, Ito T, et al. Protein kinase Cα inhibitor enhances the sensitivity of human pancreatic cancer HPAC cells to Clostridium perfringens enterotoxin via claudin-4. Cell Tissue Res. 2011;346(3):369–381. doi:10.1007/s00441-011-1287-2

110. Wu Y, Sato F, Yamada T, et al. The BHLH transcription factor DEC1 plays an important role in the epithelial-mesenchymal transition of pancreatic cancer. Int j Oncol. 2012;41(4):1337–1346. doi:10.3892/ijo.2012.1559

111. Sato M, Matsumoto M, Saiki Y, et al. BACH1 promotes pancreatic cancer metastasis by repressing epithelial genes and enhancing epithelial-mesenchymal transition. Cancer Res. 2020;80(6):1279–1292. doi:10.1158/0008-5472.CAN-18-4099

112. Michl P, Buchholz M, Rolke M, et al. Claudin-4: a new target for pancreatic cancer treatment using Clostridium perfringens enterotoxin. Gastroenterology. 2001;121(3):678–684. doi:10.1053/gast.2001.27124

113. Kakutani H, Kondoh M, Saeki R, et al. Claudin-4-targeting of diphtheria toxin fragment A using a C-terminal fragment of Clostridium perfringens enterotoxin. Europ J Pharmac Biopharm. 2010;75(2):213–217. doi:10.1016/j.ejpb.2010.03.003

114. Shim MK, Na J, Cho IK, et al. Targeting of claudin-4 by Clostridium perfringens enterotoxin-conjugated polysialic acid nanoparticles for pancreatic cancer therapy. J Cont Rel. 2021;331:434–442. doi:10.1016/j.jconrel.2021.01.031

115. Pahle J, Kobelt D, Aumann J, et al. Effective oncoleaking treatment of pancreatic cancer by claudin-targeted suicide gene therapy with clostridium perfringens enterotoxin (CPE). Cancers. 2021;13(17):4393. doi:10.3390/cancers13174393

116. Bang C, Park MG, Cho IK, et al. Liposomes targeting the cancer cell-exposed receptor, claudin-4, for pancreatic cancer chemotherapy. Biomater Res. 2023;27(1):53. doi:10.1186/s40824-023-00394-7

117. Neesse A, Hahnenkamp A, Griesmann H, et al. Claudin-4-targeted optical imaging detects pancreatic cancer and its precursor lesions. Gut. 2013;62(7):1034–1043. doi:10.1136/gutjnl-2012-302577

118. Mosley M, Knight J, Neesse A, et al. Claudin-4 SPECT imaging allows detection of aplastic lesions in a mouse model of breast cancer. J Nucl Med. 2015;56(5):745–751. doi:10.2967/jnumed.114.152496

119. Feni L, Omrane MA, Fischer M, Zlatopolskiy BD, Neumaier B, Neundorf I. Convenient preparation of (18)F-labeled peptide probes for potential claudin-4 PET imaging. Pharmaceuticals. 2017;10(4):99. doi:10.3390/ph10040099

120. Torres JB, Knight JC, Mosley MJ, et al. Imaging of claudin-4 in pancreatic ductal adenocarcinoma using a radiolabelled anti-claudin-4 monoclonal antibody. Molec Imag Biol. 2018;20(2):292–299. doi:10.1007/s11307-017-1112-8

121. Torres JB, Mosley M, Koustoulidou S, et al. Radiolabeled cCPE peptides for SPECT imaging of claudin-4 Overexpression in pancreatic cancer. J Nucl Med. 2020;61(12):1756–1763. doi:10.2967/jnumed.120.243113

122. Suzuki M, Kato-Nakano M, Kawamoto S, et al. Therapeutic antitumor efficacy of monoclonal antibody against Claudin-4 for pancreatic and ovarian cancers. Can Sci. 2009;100(9):1623–1630. doi:10.1111/j.1349-7006.2009.01239.x

123. Sasaki T, Fujiwara-Tani R, Kishi S, et al. Targeting claudin-4 enhances chemosensitivity of pancreatic ductal carcinomas. Cancer Med. 2019;8(15):6700–6708. doi:10.1002/cam4.2547

124. Yamaguchi H, Kojima T, Ito T, et al. Effects of Clostridium perfringens enterotoxin via claudin-4 on normal human pancreatic duct epithelial cells and cancer cells. Cell. Mol. Biol. Lett. 2011;16(3):385–397. doi:10.2478/s11658-011-0014-z

125. Erramilli SK, Dominik PK, Ogbu CP, Kossiakoff AA, Vecchio AJ. Structural and biophysical insights into targeting of claudin-4 by a synthetic antibody fragment. Commun. Biol. 2024;7(1):733. doi:10.1038/s42003-024-06437-6

126. Hagen SJ. Non-canonical functions of claudin proteins: beyond the regulation of cell-cell adhesions. Tissue Barriers. 2017;5(2):e1327839. doi:10.1080/21688370.2017.1327839

127. Sauer T, Pedersen MK, Ebeltoft K, Naess O. Reduced expression of Claudin-7 in fine needle aspirates from breast carcinomas correlate with grading and metastatic disease. Cytopathology. 2005;16(4):193–198. doi:10.1111/j.1365-2303.2005.00257.x

128. Nakayama F, Semba S, Usami Y, Chiba H, Sawada N, Yokozaki H. Hypermethylation-modulated downregulation of claudin-7 expression promotes the progression of colorectal carcinoma. Pathobiol. 2008;75(3):177–185. doi:10.1159/000124978

129. Lu Z, Ding L, Hong H, Hoggard J, Lu Q, Chen YH. Claudin-7 inhibits human lung cancer cell migration and invasion through ERK/MAPK signaling pathway. Exp. Cell. Res. 2011;317(13):1935–1946. doi:10.1016/j.yexcr.2011.05.019

130. Flores AR, Rêma A, Carvalho F, Lopes G, Faustino A, Dias Pereira P. Clinicopathological significance of immunoexpression of claudin-1 and claudin-7 in feline mammary carcinomas. J Comparat Pathol. 2014;151(4):339–346. doi:10.1016/j.jcpa.2014.07.006

131. Brokalaki EI, Weber F, Sotiropoulos GC, Daoudaki M, Cicinnati VR, Beckebaum S. Claudin-7 expression in hepatocellular carcinoma. Transplant Proc. 2012;44(9):2737–2740. doi:10.1016/j.transproceed.2012.09.009

132. Oshima T, Kunisaki C, Yoshihara K, et al. Reduced expression of the claudin-7 gene correlates with venous invasion and liver metastasis in colorectal cancer. Oncol Rep. 2008;19(4):953–959.

133. Jakab C, Kiss A, Schaff Z, et al. Claudin-7 protein differentiates canine cholangiocarcinoma from hepatocellular carcinoma. Histol Histopath. 2010;25(7):857–864. doi:10.14670/HH-25.857

134. Comper F, Antonello D, Beghelli S, et al. Expression pattern of claudins 5 and 7 distinguishes solid-pseudopapillary from pancreatoblastoma, acinar cell and endocrine tumors of the pancreas. Am J Surg Pathol. 2009;33(5):768–774. doi:10.1097/PAS.0b013e3181957bc4

135. Soini Y, Takasawa A, Eskelinen M, et al. Expression of claudins 7 and 18 in pancreatic ductal adenocarcinoma: association with features of differentiation. J Clin Pathol. 2012;65(5):431–436. doi:10.1136/jclinpath-2011-200400

136. Okui N, Kamata Y, Sagawa Y, et al. Claudin 7 as a possible novel molecular target for the treatment of pancreatic cancer. Pancreatology. 2019;19(1):88–96. doi:10.1016/j.pan.2018.10.009

137. Ladwein M, Pape UF, Schmidt DS, et al. The cell-cell adhesion molecule EpCAM interacts directly with the tight junction protein claudin-7. Exp. Cell. Res. 2005;309(2):345–357. doi:10.1016/j.yexcr.2005.06.013

138. Nübel T, Preobraschenski J, Tuncay H, et al. Claudin-7 regulates EpCAM-mediated functions in tumor progression. Molec Can Res. 2009;7(3):285–299. doi:10.1158/1541-7786.MCR-08-0200

139. Thuma F, Zöller M. EpCAM-associated claudin-7 supports lymphatic spread and drug resistance in rat pancreatic cancer. Internat J Can. 2013;133(4):855–866. doi:10.1002/ijc.28085

140. Kyuno D, Zhao K, Schnölzer M, Provaznik J, Hackert T, Zöller M. Claudin7-dependent exosome-promoted reprogramming of nonmetastasizing tumor cells. Internat J Can. 2019;145(8):2182–2200. doi:10.1002/ijc.32312

141. Kyuno D, Bauer N, Schnölzer M, et al. Distinct origin of claudin7 in early tumor endosomes affects exosome assembly. Int J Bio Sci. 2019;15(10):2224–2239. doi:10.7150/ijbs.35347

142. Günzel D, Fromm M. Claudins and other tight junction proteins. Compr Physiol. 2012;2(3):1819–1852.

143. Rosenthal R, Günzel D, Theune D, Czichos C, Schulzke JD, Fromm M. Water channels and barriers formed by claudins. Ann. N.Y. Acad. Sci. 2017;1397(1):100–109. doi:10.1111/nyas.13383

144. Heinemann U, Schuetz A. Structural features of tight-junction proteins. Int J Mol Sci. 2019;20(23):6020. doi:10.3390/ijms20236020

145. Wang Z, Wang A, Gong Z, Biviano I, Liu H, Hu J. Plasma claudin-3 is associated with tumor necrosis factor-alpha-induced intestinal endotoxemia in liver disease. Clin Res Hepatol Gastroenterol. 2019;43(4):410–416. doi:10.1016/j.clinre.2018.11.014

146. Baier FA, Sánchez-Taltavull D, Yarahmadov T, et al. Loss of claudin-3 impairs hepatic metabolism, biliary barrier function, and cell proliferation in the murine liver. CMGH. 2021;12(2):745–767. doi:10.1016/j.jcmgh.2021.04.003

147. Matsumoto K, Imasato M, Yamazaki Y, et al. Claudin 2 deficiency reduces bile flow and increases susceptibility to cholesterol gallstone disease in mice. Gastroenterology. 2014;147(5):1134–1145.e1110. doi:10.1053/j.gastro.2014.07.033

148. Tanaka H, Imasato M, Yamazaki Y, et al. Claudin-3 regulates bile canalicular paracellular barrier and cholesterol gallstone core formation in mice. J Hepatol. 2018;69(6):1308–1316. doi:10.1016/j.jhep.2018.08.025

149. Zheng A, Yuan F, Li Y, et al. Claudin-6 and claudin-9 function as additional coreceptors for hepatitis C virus. J Virol. 2007;81(22):12465–12471. doi:10.1128/JVI.01457-07

150. Sakaguchi T, Suzuki S, Higashi H, et al. Expression of tight junction protein claudin-5 in tumor vessels and sinusoidal endothelium in patients with hepatocellular carcinoma. J Surg Res. 2008;147(1):123–131. doi:10.1016/j.jss.2007.07.013

151. Patonai A, Erdélyi-Belle B, Korompay A, et al. Claudins and tricellulin in fibrolamellar hepatocellular carcinoma. Virchows Archiv. 2011;458(6):679–688. doi:10.1007/s00428-011-1077-y

152. Huang L, Zhao C, Sun K, et al. Downregulation of CLDN6 inhibits cell proliferation, migration, and invasion via regulating EGFR/AKT/mTOR signalling pathway in hepatocellular carcinoma. Cell Biochem. Funct. 2020;38(5):541–548. doi:10.1002/cbf.3489

153. Lu Y, Dang Q, Bo Y, et al. The Expression of CLDN6 in hepatocellular carcinoma tissue and the effects of CLDN6 on biological phenotypes of hepatocellular carcinoma cells. J Cancer. 2021;12(18):5454–5463. doi:10.7150/jca.55727

154. Huang GW, Ding X, Chen SL, Zeng L. Expression of claudin 10 protein in hepatocellular carcinoma: impact on survival. J Cancer Res Clin Oncol. 2011;137(8):1213–1218. doi:10.1007/s00432-011-0987-z

155. Ip YC, Cheung ST, Lee YT, Ho JC, Fan ST. Inhibition of hepatocellular carcinoma invasion by suppression of claudin-10 in HLE cells. Mol Cancer Ther. 2007;6(11):2858–2867. doi:10.1158/1535-7163.MCT-07-0453

156. Cheung ST, Leung KL, Ip YC, et al. Claudin-10 expression level is associated with recurrence of primary hepatocellular carcinoma. Clinical Can Res. 2005;11(2):551–556. doi:10.1158/1078-0432.551.11.2

157. Li CP, Cai MY, Jiang LJ, et al. CLDN14 is epigenetically silenced by EZH2-mediated H3K27ME3 and is a novel prognostic biomarker in hepatocellular carcinoma. Carcinogenesis. 2016;37(6):557–566. doi:10.1093/carcin/bgw036

158. Jiang L, Yang YD, Fu L, 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:10.18632/oncotarget.2288

159. MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev. Cell. 2009;17(1):9–26. doi:10.1016/j.devcel.2009.06.016

160. Ikeda C, Haga H, Makino N, et al. Utility of Claudin-3 in extracellular vesicles from human bile as biomarkers of cholangiocarcinoma. Sci Rep. 2021;11(1):1195. doi:10.1038/s41598-021-81023-y

161. Lee JH, Kim KS, Kim TJ, et al. Immunohistochemical analysis of claudin expression in pancreatic cystic tumors. Oncol Rep. 2011;25(4):971–978. doi:10.3892/or.2011.1132

162. Jiang F, Li S, Wang X, Deng Y, Peng S. DPP10-AS1-mediated downregulation of MicroRNA-324-3p is conducive to the malignancy of pancreatic cancer by enhancing CLDN3 expression. Pancreas. 2022;51(9):1201–1210. doi:10.1097/MPA.0000000000002164

163. Borka K, Kaliszky P, Szabó E, et al. Claudin expression in pancreatic endocrine tumors as compared with ductal adenocarcinomas. Virchows Archiv. 2007;450(5):549–557. doi:10.1007/s00428-007-0406-7

164. Gurevich LE, Kazantseva IA, Sokolova IN, et al. Solid pseudopapillary tumors of the pancreas: clinical and morphological characteristics, specific features of their immunophenotype, and diagnostic problems. Arkhiv patologii. 2014;76(5):44–54.

165. Zheng HY, Shi YH, Zhang LF, Chen YZ. Evaluation of the expression and significance of Claudin-5 and CD99 in solid-pseudopapillary neoplasms and neuroendocrine tumors of pancreas. Zhonghua Bing li xue za zhi. 2013;42(6):372–375. doi:10.3760/cma.j.issn.0529-5807.2013.06.004

166. Jakab C, Rusvai M, Gálfi P, Halász J, Kulka J. Expression of claudin-5 in canine pancreatic acinar cell carcinoma - An immunohistochemical study. Acta veterinaria Hungarica. 2011;59(1):87–98. doi:10.1556/avet.59.2011.1.8

167. Liu H, Wang M, Liang N, Guan L. Claudin-9 enhances the metastatic potential of hepatocytes via Tyk2/Stat3 signaling. Turkish J Gastroenterol. 2019;30(8):722–731. doi:10.5152/tjg.2019.18513

168. Sun L, Feng L, Cui J. Increased expression of claudin-17 promotes a malignant phenotype in hepatocyte via Tyk2/Stat3 signaling and is associated with poor prognosis in patients with hepatocellular carcinoma. Diagn. Pathol. 2018;13(1):72. doi:10.1186/s13000-018-0749-1

169. Yang J, Liu X, Yuan X, Wang Z. miR-99b promotes metastasis of hepatocellular carcinoma through inhibition of claudin 11 expression and may serve as a prognostic marker. Oncol Rep. 2015;34(3):1415–1423. doi:10.3892/or.2015.4104

170. Zhang Y, Fang Y, Ma L, et al. LINC00857 regulated by ZNF460 enhances the expression of CLDN12 by sponging miR-150-5p and recruiting SRSF1 for alternative splicing to promote epithelial-mesenchymal transformation of pancreatic adenocarcinoma cells. RNA Biol. 2022;19(1):548–559. doi:10.1080/15476286.2021.1992995

171. Hashimoto Y, Hata T, Tada M, et al. Safety evaluation of a human chimeric monoclonal antibody that recognizes the extracellular loop domain of claudin-2. Europ J Pharmac Sci. 2018;117:161–167. doi:10.1016/j.ejps.2018.02.016

172. Kim SO, Choi YH. The ethyl alcohol extract of Hizikia fusiforme inhibits matrix metalloproteinase activity and regulates tight junction related protein expression in Hep3B human hepatocarcinoma cells. Journal of Medicinal Food. 2010;13(1):31–38. doi:10.1089/jmf.2009.1233

173. Hashimoto Y, Yagi K, Kondoh M. Roles of the first-generation claudin binder, Clostridium perfringens enterotoxin, in the diagnosis and claudin-targeted treatment of epithelium-derived cancers. Pflugers Archiv. 2017;469(1):45–53. doi:10.1007/s00424-016-1878-6

174. Stadler CR, Ellinghaus U, Fischer L, et al. Preclinical efficacy and pharmacokinetics of an RNA-encoded T cell-engaging bispecific antibody targeting human claudin 6. Sci, trans med. 2024;16(748):eadl2720. doi:10.1126/scitranslmed.adl2720

175. Niimi T, Nagashima K, Ward JM, et al. 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:10.1128/MCB.21.21.7380-7390.2001

176. Micke P, Mattsson JS, Edlund K, et al. Aberrantly activated claudin 6 and 18.2 as potential therapy targets in non-small-cell lung cancer. Internat J Can. 2014;135(9):2206–2214. doi:10.1002/ijc.28857

177. Hagen SJ, Ang LH, Zheng Y, et al. Loss of tight junction protein claudin 18 promotes progressive neoplasia development in mouse stomach. Gastroenterology. 2018;155(6):1852–1867. doi:10.1053/j.gastro.2018.08.041

178. Sahin U, Koslowski M, Dhaene K, et al. Claudin-18 splice variant 2 is a pan-cancer target suitable for therapeutic antibody development. Clinical Can Res. 2008;14(23):7624–7634. doi:10.1158/1078-0432.CCR-08-1547

179. Zhang SJ, Feng JF, Wang L, et al. miR-1303 targets claudin-18 gene to modulate proliferation and invasion of gastric cancer cells. Dig Dis Sci. 2014;59(8):1754–1763. doi:10.1007/s10620-014-3107-5

180. Dottermusch M, Krüger S, Behrens HM, Halske C, Röcken C. Expression of the potential therapeutic target claudin-18.2 is frequently decreased in gastric cancer: results from a large Caucasian cohort study. Virchows Archiv. 2019;475(5):563–571. doi:10.1007/s00428-019-02624-7

181. Wang C, Wang Y, Chen J, et al. CLDN18.2 expression and its impact on prognosis and the immune microenvironment in gastric cancer. BMC Gastroenterol. 2023;23(1):283. doi:10.1186/s12876-023-02924-y

182. Kayikcioglu E, Yüceer RO, Cetin B, Yüceer K, Karahan N. Prognostic value of claudin 18.2 expression in gastric adenocarcinoma. World J Gastroint Oncol. 2023;15(2):343–351. doi:10.4251/wjgo.v15.i2.343

183. Ogawa H, Abe H, Yagi K, Seto Y, Ushiku T. Claudin-18 status and its correlation with HER2 and PD-L1 expression in gastric cancer with peritoneal dissemination. Gast Can. 2024;27(4):802–810. doi:10.1007/s10120-024-01505-6

184. Choi E, Shin J, Ryu MH, Kim HD, Park YS. Heterogeneity of claudin 18.2 expression in metastatic gastric cancer. Sci Rep. 2024;14(1):17648. doi:10.1038/s41598-024-68411-w

185. Li J, Zhang Y, Hu D, Gong T, Xu R, Gao J. Analysis of the expression and genetic alteration of CLDN18 in gastric cancer. Aging. 2020;12(14):14271–14284. doi:10.18632/aging.103457

186. Suzuki K, Sentani K, Tanaka H, et al. Deficiency of stomach-type claudin-18 in mice induces gastric tumor formation independent of H pylori infection. CMGH. 2019;8(1):119–142. doi:10.1016/j.jcmgh.2019.03.003

187. Caron TJ, Scott KE, Sinha N, et al. Claudin-18 loss alters transcellular chloride flux but not tight junction ion selectivity in gastric epithelial cells. CMGH. 2021;11(3):783–801. doi:10.1016/j.jcmgh.2020.10.005

188. Liu S, Zhang Z, Jiang L, Zhang M, Zhang C, Shen L. Claudin-18.2 mediated interaction of gastric Cancer cells and Cancer-associated fibroblasts drives tumor progression. Cell Commun Signal. 2024;22(1):27. doi:10.1186/s12964-023-01406-8

189. Nakayama I, Shinozaki E, Sakata S, et al. Enrichment of CLDN18-ARHGAP fusion gene in gastric cancers in young adults. Can Sci. 2019;110(4):1352–1363. doi:10.1111/cas.13967

190. Kubota Y, Kawazoe A, Mishima S, et al. Comprehensive clinical and molecular characterization of claudin 18.2 expression in advanced gastric or gastroesophageal junction cancer. ESMO open. 2023;8(1):100762. doi:10.1016/j.esmoop.2022.100762

191. Zhang F, Sahu V, Peng K, et al. Recurrent RhoGAP gene fusion CLDN18-ARHGAP26 promotes RHOA activation and focal adhesion kinase and YAP-TEAD signalling in diffuse gastric cancer. Gut. 2024;73(8):1280–1291. doi:10.1136/gutjnl-2023-329686

192. Jia K, Chen Y, Sun Y, et al. Multiplex immunohistochemistry defines the tumor immune microenvironment and immunotherapeutic outcome in CLDN18.2-positive gastric cancer. BMC Med. 2022;20(1):223. doi:10.1186/s12916-022-02421-1

193. Xu X, Li Y, Zhang R, et al. Jianpi Yangzheng decoction suppresses gastric cancer progression via modulating the miR-448/CLDN18.2 mediated YAP/TAZ signaling. J Ethnopharmacol. 2023;311:116450. doi:10.1016/j.jep.2023.116450

194. Qi C, Guo R, Chen Y, et al. (68)Ga-NC-BCH Whole-Body PET imaging rapidly targets claudin18.2 in lesions in gastrointestinal cancer patients. J Nucl Med. 2024;65(6):856–863. doi:10.2967/jnumed.123.267110

195. Zhang J, Dong R, Shen L. Evaluation and reflection on claudin 18.2 targeting therapy in advanced gastric cancer. Chin J Can Res. 2020;32(2):263–270. doi:10.21147/j.issn.1000-9604.2020.02.13

196. Niclauss N, Gütgemann I, Dohmen J, Kalff JC, Lingohr P. Novel biomarkers of gastric adenocarcinoma: current research and future perspectives. Cancers. 2021;13(22):5660. doi:10.3390/cancers13225660

197. Fan L, Chong X, Zhao M, et al. Ultrasensitive gastric cancer circulating tumor cellular CLDN18.2 RNA detection based on a molecular beacon. Anal. Chem. 2021;93(2):665–670. doi:10.1021/acs.analchem.0c04055

198. Hu G, Zhu W, Liu Y, et al. Development and comparison of three (89)Zr-labeled anti-CLDN18.2 antibodies to noninvasively evaluate CLDN18.2 expression in gastric cancer: a preclinical study. Eur J Nucl Med Mol Imaging. 2022;49(8):2634–2644. doi:10.1007/s00259-022-05739-3

199. Zhao C, Rong Z, Ding J, et al. Targeting Claudin 18.2 using a highly specific antibody enables cancer diagnosis and guided surgery. Mol Pharmaceut. 2022;19(10):3530–3541. doi:10.1021/acs.molpharmaceut.1c00947

200. Matsuishi A, Nakajima S, Saito M, et al. The impact of CLDN18.2 expression on effector cells mediating antibody-dependent cellular cytotoxicity in gastric cancer. Sci Rep. 2024;14(1):17916. doi:10.1038/s41598-024-68970-y

201. Lordick F, Van Cutsem E, Shitara K, et al. Health-related quality of life in patients with CLDN18.2-positive, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma: results from the SPOTLIGHT and GLOW clinical trials. ESMO open. 2024;9(8):103663. doi:10.1016/j.esmoop.2024.103663

202. Kyuno D, Takasawa A, Takasawa K, et al. Claudin-18.2 as a therapeutic target in cancers: cumulative findings from basic research and clinical trials. Tissue Barriers. 2022;10(1):1967080. doi:10.1080/21688370.2021.1967080

203. Nishibata T, Weng J, Omori K, et al. Effect of anti-claudin 18.2 monoclonal antibody zolbetuximab alone or combined with chemotherapy or programmed cell death-1 blockade in syngeneic and xenograft gastric cancer models. J Pharmacol Sci. 2024;155(3):84–93. doi:10.1016/j.jphs.2024.04.004

204. Shah MA, Shitara K, Ajani JA, et al. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, Phase 3 GLOW trial. Nature Med. 2023;29(8):2133–2141. doi:10.1038/s41591-023-02465-7

205. Zhou KI, Strickler JH, Chen H. Targeting Claudin-18.2 for cancer therapy: updates from 2024 ASCO annual meeting. J Hematol Oncol. 2024;17(1):73. doi:10.1186/s13045-024-01595-w

206. Yue J, Shao S, Zhou J, et al. A bispecific antibody targeting HER2 and CLDN18.2 eliminates gastric cancer cells expressing dual antigens by enhancing the immune effector function. Invest New Drugs. 2024;42(1):106–115. doi:10.1007/s10637-024-01417-3

207. Ma Z, Zhou Z, Duan W, et al. DR30318, a novel tri-specific T cell engager for Claudin 18.2 positive cancers immunotherapy. Can Immunol Immunoth. 2024;73(5):82. doi:10.1007/s00262-024-03673-x

208. Qi C, Liu C, Gong J, et al. Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial final results. Nature Med. 2024;30(8):2224–2234. doi:10.1038/s41591-024-03037-z

209. Zeng Z, Li L, Tao J, et al. [(177)Lu]Lu-labeled anti-claudin-18.2 antibody demonstrated radioimmunotherapy potential in gastric cancer mouse xenograft models. Eur J Nucl Med Mol Imaging. 2024;51(5):1221–1232. doi:10.1007/s00259-023-06561-1

210. Türeci Ӧ, Mitnacht-Kraus R, Wöll S, Yamada T, Sahin U. Characterization of zolbetuximab in pancreatic cancer models. Oncoimmunology. 2019;8(1):e1523096. doi:10.1080/2162402X.2018.1523096

211. Zhu G, Foletti D, Liu X, et al. Targeting CLDN18.2 by CD3 Bispecific and ADC modalities for the treatments of gastric and pancreatic cancer. Sci Rep. 2019;9(1):8420. doi:10.1038/s41598-019-44874-0

212. Hong JY, An JY, Lee J, et al. Claudin 18.2 expression in various tumor types and its role as a potential target in advanced gastric cancer. Transl Cancer Res. 2020;9(5):3367–3374. doi:10.21037/tcr-19-1876

213. Hu R, Zhang W, Han Z, et al. Identification of immune-related target and prognostic biomarkers in PBMC of hepatocellular carcinoma. BMC Gastroenterol. 2023;23(1):234. doi:10.1186/s12876-023-02843-y

214. Tanaka M, Shibahara J, Fukushima N, et al. Claudin-18 is an early-stage marker of pancreatic carcinogenesis. J Histoch Cytoch. 2011;59(10):942–952. doi:10.1369/0022155411420569

215. Kyuno D, Yamaguchi H, Ito T, et al. Targeting tight junctions during epithelial to mesenchymal transition in human pancreatic cancer. World J Gastroenterol. 2014;20(31):10813–10824. doi:10.3748/wjg.v20.i31.10813

216. Wang X, Zhang CS, Dong XY, et al. Claudin 18.2 is a potential therapeutic target for zolbetuximab in pancreatic ductal adenocarcinoma. World J Gastroint Oncol. 2022;14(7):1252–1264. doi:10.4251/wjgo.v14.i7.1252

217. Zhang Z, Liu X, Zhou L, Zhang M, Liang Z. Investigation of clinical application of claudin 18 isoform 2 in pancreatic ductal adenocarcinoma: a retrospective analysis of 302 Chinese patients. Histol Histopath. 2022;37(10):1031–1040. doi:10.14670/HH-18-477

218. Karanjawala ZE, Illei PB, Ashfaq R, 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:10.1097/PAS.0b013e31815701f3

219. Williams HL, Dias Costa A, Zhang J, et al. Spatially resolved single-cell assessment of pancreatic cancer expression subtypes reveals co-expressor phenotypes and extensive intratumoral heterogeneity. Cancer Res. 2023;83(3):441–455. doi:10.1158/0008-5472.CAN-22-3050

220. Sanada Y, Hirose Y, Osada S, et al. Immunohistochemical study of claudin 18 involvement in intestinal differentiation during the progression of intraductal papillary mucinous neoplasm. Anticancer Res. 2010;30(7):2995–3003.

221. Li WT, Jeng YM, Yang CY. Claudin-18 as a marker for identifying the stomach and pancreatobiliary tract as the primary sites of metastatic adenocarcinoma. Am J Surg Pathol. 2020;44(12):1643–1648. doi:10.1097/PAS.0000000000001583

222. Yang YJ, Jeng YM, Yang CY, Hu HW. Claudin-18 immunohistochemical staining facilitates the identification of metastatic carcinoma of gastric or pancreatic origin in effusion specimens. Applied Immunohistoch Molecul Morphol. 2022;30(1):8–13. doi:10.1097/PAI.0000000000000971

223. Tokumitsu T, Sato Y, Yamashita A, et al. Immunocytochemistry for Claudin-18 and Maspin in biliary brushing cytology increases the accuracy of diagnosing pancreatobiliary malignancies. Cytopathology. 2017;28(2):116–121. doi:10.1111/cyt.12368

224. De Sanctis F, Dusi S, Caligola S, et al. Expression of the membrane tetraspanin claudin 18 on cancer cells promotes T lymphocyte infiltration and antitumor immunity in pancreatic cancer. Immunity. 2024;57(6):1378–1393.e1314. doi:10.1016/j.immuni.2024.04.021

225. Ito T, Kojima T, Yamaguchi H, 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:10.1002/jcb.23095

226. Kojima T, Sawada N. Regulation of tight junctions in human normal pancreatic duct epithelial cells and cancer cells. Ann. N.Y. Acad. Sci. 2012;1257:85–92. doi:10.1111/j.1749-6632.2012.06579.x

227. Lyu SI, Fretter C, Simon AG, et al. Extent and clinical significance of the therapy-relevant tight junction protein Claudin 18.2 in pancreatic ductal adenocarcinoma - real-world evidence. Transl Oncol. 2024;47:102044. doi:10.1016/j.tranon.2024.102044

228. Zhong W, Lu Y, Ma Z, et al. Development of a humanized VHH based recombinant antibody targeting claudin 18.2 positive cancers. Front Immunol. 2022;13:885424. doi:10.3389/fimmu.2022.885424

229. Katoh M, Katoh M. Precision medicine for human cancers with Notch signaling dysregulation (Review). IntJ Mol Med. 2020;45(2):279–297. doi:10.3892/ijmm.2019.4418

230. Liu Y, Sun Y, Wang P, et al. FAP-targeted CAR-T suppresses MDSCs recruitment to improve the antitumor efficacy of claudin18.2-targeted CAR-T against pancreatic cancer. J Transl Med. 2023;21(1):255. doi:10.1186/s12967-023-04080-z

231. Wang S, Qi C, Ding J, et al. First-in-human CLDN18.2 functional diagnostic pet imaging of digestive system neoplasms enables whole-body target mapping and lesion detection. Eur J Nucl Med Mol Imaging. 2023;50(9):2802–2817. doi:10.1007/s00259-023-06234-z

Creative Commons License © 2024 The Author(s). This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, 3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

Download Article [PDF]