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.

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