CLDN18.2: A Key Player in Gastric and Pancreatic Cancer
What's the Tight Junction Protein?
Tight junction proteins, also known as Tight Junction Proteins, comprise a category of proteins primarily situated on the cell membrane. They are prominently found within the tight junctions that establish connections between epithelial cells and endothelial cell layers. These cellular junctions give rise to a physical barrier that steadfastly binds neighboring cell membranes, thus constraining the unimpeded diffusion of fluids, ions, molecules, and cells. This intricate architecture holds pivotal significance in upholding the integrity of tissue barriers and cellular polarity.
Among the notable members of tight junction proteins are Claudins, Occludin, Junctional Adhesion Molecules (JAMs), and Zonula Occludens (ZO) proteins. These diverse proteins perform distinct roles in both the formation and functionality of tight junctions.
Decoding CLDN18.2: An Exclusive Marker Protein
Claudin18.2 (CLDN18.2) stands as a remarkably discerning marker protein, exclusively expressed in differentiated gastric mucosal membrane epithelial cells. Its presence is markedly limited in normal healthy tissues, and it remains absent in undifferentiated gastric stem cells[1]. Within the realms of normal tissue, CLDN18.2 typically resides within the tight junctions of gastric mucosal cells[2-4]. A critical role of CLDN18.2 is to uphold the barrier function of the gastric mucosa, thereby preventing the undue leakage of H+ in gastric acid via paracellular pathways[5]. Furthermore, the discovery of CLDN18.2 overexpression across several cancer types, including pancreatic cancer (PC)[6], esophageal cancer, ovarian adenocarcinoma, and lung cancers, underscores its potential for diagnosing and treating various other tumors.
The Structure of CLDN18.2
Claudin-18 is a major component of tight junctions located on the cell membrane surface; it plays an important role in the maintenance of cell polarity and barrier function and promotes acid resistance[7-9]. For example, in the stomach, claudin-18 normally forms a paracellular barrier against H(+), promotes acid resistance, and causes paracellular H(+) leakage, persistent upregulation of proinflammatory cytokines and atrophic gastritis in mice[10]. The human CLDN18 gene locus on chromosome 3q22 has a molecular weight of approximately 35 kb and contains 6 exons and 5 introns. The first exon of CLDN18 can be alternatively spliced, forming two different splice mutants (CLDN18.1 and CLDN18.2) that have highly homologous amino acid sequences[11]. The transmembrane protein CLDN18 consists of two extracellular loops (ECLs), four transmembrane domains and a cytoplasmic domain. Both the C-terminus and the N-terminus of CLDN 18 are located in the cytoplasm. Two CLDN18 protein isoforms are expressed in a tissue-specific manner—CLDN18.1 and CLDN18.2 are specifically expressed in normal stomach and lung tissues, respectively[12]. CLDN18 is also expressed in cancer tissues and has altered functions that are linked to tumour formation, proliferation, invasion and migration[13-15].
The Function of CLDN18.2
First, CLDN18.2 actively participates in the construction and sustenance of tight junctions, pivotal structures situated between cell layers. Intercellular junctions, which encompass cell membrane protein complexes, tightly unite the membranes of adjoining cells. This configuration establishes a formidable barrier that thwarts the unhindered movement of substances like liquids, ions, and microorganisms. Collaborating with other tight junction proteins, CLDN18.2 contributes to erecting this protective barrier. This function serves to uphold the cohesion of tissues and organs while deterring the infiltration of detrimental substances.
Second, CLDN18.2 assumes a crucial role in nurturing cell polarity and promoting interlayer adhesion. Cell polarity pertains to the phenomenon where distinct regions within a cell encompass different functions and attributes. In parallel, interlayer adhesion facilitates the harmonious coordination of structure and function between cell layers. The presence of CLDN18.2 reinforces this cellular polarity and adhesion, ensuring accurate cellular alignment within tissues and fostering intercellular adhesion.
In addition, CLDN18.2 may also partake in cell signaling activities. Recent research suggests that tight junction proteins potentially engage in the modulation of intracellular signaling pathways, influencing the physiological functions of cells. Although this realm remains under exploration, it hints at the prospective role of CLDN18.2 in intracellular signaling processes.
In summation, CLDN18.2, functioning as a tight junction protein, stands as a cornerstone in upholding the architecture and functionality of gastric mucosal epithelial cells. Its engagement spans barrier establishment, preservation of cell layer integrity, assurance of cell polarity and interlayer adhesion, and a potential impact on intracellular signaling. These multifaceted functions collectively underscore the vital importance of CLDN18.2 in preserving the normal function and structure of bodily tissues.
Exploring the Impact of CLDN18.2 in Cancer
The pivotal role of CLDN18.2 (Claudin 18.2) in cancer has garnered considerable attention, particularly within the domain of gastric cancer. Gastric cancer, a malignancy, is significantly influenced by the presence of CLDN18.2, exerting a substantial influence on its progression and therapeutic approaches.
Research indicates a prevalent upregulation of CLDN18.2 expression in gastric cancer tissues. This heightened expression often correlates with the intricate process of gastric cancer development and invasion. Elevated CLDN18.2 levels might trigger alterations within tight junctions, thereby affecting both barrier functionality and intercellular adhesion. Such changes may result in abnormal cell proliferation, migration, and invasion, thus fostering the initiation and advancement of gastric cancer.
Moreover, given the prominence of CLDN18.2 expression in gastric cancer cells, researchers have begun to consider it as a promising target for precision therapies. The development of therapeutic agents designed to recognize and intervene with CLDN18.2 holds potential in selectively curtailing the proliferation and migration of gastric cancer cells. Ongoing clinical trials, including the use of monoclonal antibodies like zolbetuximab targeting CLDN18.2, signify a pioneering attempt to employ this precise therapeutic strategy for inhibiting the expansion and dissemination of gastric cancer.
However, despite the extensive attention surrounding the prospective role of CLDN18.2 in gastric cancer treatment, further investigations are imperative. A comprehensive understanding of its precise mechanisms of action within cancer development, as well as strategies for optimizing its utilization as a therapeutic target, are essential to enhance patient outcomes and prognoses. These ongoing studies are poised to unveil novel avenues and tactics for the comprehensive management and treatment of gastric cancer.
CLDN18.2 and Gastric Cancer
CLDN18.2's pivotal role in gastric cancer cannot be understated. Research underscores that heightened CLDN18.2 expression might correlate with increased adhesion, migration, and invasiveness of gastric cancer cells. This phenomenon could facilitate the traversing of tissue barriers by cancer cells, leading to infiltration of adjacent tissues and blood vessels, thereby propelling tumor progression and dissemination. Moreover, the elevated presence of CLDN18.2 might impact the severity and prognosis of gastric cancer, as it could influence the tumor's biological behavior and clinical presentation.
Given its exclusive expression within gastric cancer cells, CLDN18.2 has emerged as an attractive therapeutic target for gastric cancer treatment. Scientists are diligently crafting interventions that disrupt CLDN18.2's function, thereby curbing the expansion and spread of tumors. Currently, monoclonal antibody medications targeting CLDN18.2, such as zolbetuximab, are undergoing clinical trials. These pioneering drugs have the potential to specifically hinder the proliferation and migration of gastric cancer cells by precisely targeting and interfering with CLDN18.2.
The intricate interplay between CLDN18.2 and gastric cancer presents a promising avenue for therapeutic innovation. As research continues to unveil the nuanced dynamics at play, novel treatment strategies harnessing CLDN18.2's potential hold the key to revolutionizing the management of gastric cancer, offering renewed hope for patients and enhancing their quality of life.
CLDN18.2 and Pancreatic Cancer
In 2012, GLOBOCAN reported a global count of 338,000 individuals grappling with pancreatic cancer, making it the 11th most prevalent cancer type. This malignancy contributes to around 331,000 annual fatalities, ranking as the seventh leading cause of cancer-related death. The statistical findings from China's National Cancer Center in 2021 reveal pancreatic cancer's prevalence as the seventh most commonly occurring malignancy in males, eleventh in females, and sixth in terms of cancer-associated mortality. Notably, its incidence displays stark geographical variations, with developed nations bearing a higher burden. Specifically, North America (74000/100,000 individuals) and Western Europe (73000/100,000 individuals) exhibit the highest rates, followed by various European regions and Australia (65000/100,000 individuals), while Central Africa and Central and South Asia display the lowest rates (10000/100,000 individuals). Over decades, both the incidence and fatality rates of pancreatic cancer have surged globally, with a chillingly low 5-year survival rate of 5-7%.
Heightened CLDN18.2 expression potentially fuels the heightened proliferation, invasion, and migration of pancreatic cancer cells. This elevation might facilitate cancer cells in surmounting tissue barriers, infiltrating blood vessels, and accessing lymphatic vessels, ultimately facilitating tumor dissemination and metastasis. Additionally, the degree of CLDN18.2 expression could impact the prognoses of pancreatic cancer patients, with elevated levels potentially correlating with poorer survival rates and prognostic outcomes.
CLDN Expression Regulation in Cancer and Tumorigenesis
The current understanding of the mechanisms through which CLDNs, including CLDN18.2, contribute to tumorigenesis remains somewhat unclear. Research primarily suggests that CLDNs activate diverse signaling pathways and proteases that directly or indirectly facilitate tumorigenesis.
One direct mechanism involves the cooperation of CLDNs with other molecules, such as EpCAM, MT-MMPs, ADAM10, and integrins. This collaboration prompts CLDNs to engage in signaling, extracellular matrix (ECM) degradation, and receptor cleavage.
Another direct approach encompasses the interaction of transcription factors (TFs), like YAP/TAZ and β-catenin, resulting in the nuclear accumulation of these TFs.
The indirect mechanism involves two molecules. Firstly, proteases like MMPs cleave ECM, releasing growth factors (GFs) that activate pathways like RTK/PI3K, MAPK, TGF-β/SMAD, and JAK/STAT. Secondly, protein kinases, including SFK, ABL, and Tyk2, phosphorylate downstream molecules. However, the precise mechanisms of action for these processes are not yet fully elucidated.
These interconnected signaling pathways collectively synergize with signals from CLDNs, fostering an environment that promotes tumorigenesis.
CLND18.2 Protein
Recombinant Human Claudin-18.2 (CLDN18.2) Protein (His), Active
This product is detected by Mouse anti-6*His monoclonal antibody.The three bands respectively correspond to monomer, Homodimer, Homotrimer
Synonyms:CLDN18; UNQ778/PRO1572; Claudin-18
References:
[1] Singh P, Toom S, Huang Y. Anti-claudin 18.2 antibody as new targeted therapy for advanced gastric cancer. J Hematol Oncol 2017;10(1):105.
[2] 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
[3] TĂĽreci O, Koslowski M, Helftenbein G, et al. Claudin-18 gene structure, regulation, and expression is evolutionary conserved in mammals. Gene. 2011;481(2):83-92. doi:10.1016/j.gene.2011.04.007
[4] Sahin U, Koslowski M, Dhaene K, et al. Claudin-18 splice variant 2 is a pan-cancer target suitable for therapeutic antibody development. Clin Cancer Res. 2008;14(23):7624-7634. doi:10.1158/1078-0432.CCR-08-1547
[5] Hayashi D, Tamura A, Tanaka H, Yamazaki Y, Watanabe S, Suzuki K, et al. Deficiency of claudin-18 causes paracellular H+ leakage, up-regulation of interleukin-1β, and atrophic gastritis in mice. Gastroenterol. 2012;142(2):292–304.
[6] Tanaka M, Shibahara J, Fukushima N, et al. Claudin-18 is an early-stage marker of pancreatic carcinogenesis. J Histochem Cytochem. 2011;59(10):942-952. doi:10.1369/0022155411420569
[7] 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
[8] LaFemina MJ, Sutherland KM, Bentley T, et al. Claudin-18 deficiency results in alveolar barrier dysfunction and impaired alveologenesis in mice. Am J Respir Cell Mol Biol. 2014;51(4):550-558. doi:10.1165/rcmb.2013-0456OC
[9] Li G, Flodby P, Luo J, et al. Knockout mice reveal key roles for claudin 18 in alveolar barrier properties and fluid homeostasis. Am J Respir Cell Mol Biol. 2014;51(2):210-222. doi:10.1165/rcmb.2013-0353OC
[10] Hayashi D, Tamura A, Tanaka H, et al. Deficiency of claudin-18 causes paracellular H+ leakage, up-regulation of interleukin-1β, and atrophic gastritis in mice. Gastroenterology. 2012;142(2):292-304. doi:10.1053/j.gastro.2011.10.040
[11] TĂĽreci O, Koslowski M, Helftenbein G, et al. Claudin-18 gene structure, regulation, and expression is evolutionary conserved in mammals. Gene. 2011;481(2):83-92. doi:10.1016/j.gene.2011.04.007
[12] Sato K, Matsumoto I, Suzuki K, et al. Deficiency of lung-specific claudin-18 leads to aggravated infection with Cryptococcus deneoformans through dysregulation of the microenvironment in lungs. Sci Rep. 2021;11(1):21110. Published 2021 Oct 26. doi:10.1038/s41598-021-00708-6
[13] Oshima T, Shan J, Okugawa T, et al. Down-regulation of claudin-18 is associated with the proliferative and invasive potential of gastric cancer at the invasive front. PLoS One. 2013;8(9):e74757. Published 2013 Sep 20. doi:10.1371/journal.pone.0074757
[14] Takasawa K, Takasawa A, Osanai M, et al. Claudin-18 coupled with EGFR/ERK signaling contributes to the malignant potentials of bile duct cancer. Cancer Lett. 2017;403:66-73. doi:10.1016/j.canlet.2017.05.033
[15] 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
[16] Chen J, Xu Z, Hu C, et al. Targeting CLDN18.2 in cancers of the gastrointestinal tract: New drugs and new indications. Front Oncol. 2023;13:1132319. Published 2023 Mar 10. doi:10.3389/fonc.2023.1132319
[17] Li J. Context-Dependent Roles of Claudins in Tumorigenesis. Front Oncol. 2021;11:676781. Published 2021 Jul 20. doi:10.3389/fonc.2021.676781
