Expression patterns of claudins in cancer
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PROVIDER: S-EPMC10637965 | biostudies-literature | 2023 Oct
REPOSITORIES: biostudies-literature
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Project description:Despite recent improvements in diagnostic ability and treatment strategies, advanced gastric cancer (GC) has a high frequency of recurrence and metastasis, with poor prognosis. To improve the treatment results of GC, the search for new treatment targets from proteins related to epithelial-mesenchymal transition (EMT) and cell-cell adhesion is currently being conducted. EMT plays an important role in cancer metastasis and is initiated by the loss of cell-cell adhesion, such as tight junctions (TJs), adherens junctions, desmosomes, and gap junctions. Among these, claudins (CLDNs) are highly expressed in some cancers, including GC. Abnormal expression of CLDN1, CLDN2, CLDN3, CLDN4, CLDN6, CLDN7, CLDN10, CLDN11, CLDN14, CLDN17, CLDN18, and CLDN23 have been reported. Among these, CLDN18 is of particular interest. In The Cancer Genome Atlas, GC was classified into four new molecular subtypes, and CLDN18-ARHGAP fusion was observed in the genomically stable type. An anti-CLDN18.2 antibody drug was recently developed as a therapeutic drug for GC, and the results of clinical trials are highly predictable. Thus, CLDNs are highly expressed in GC as TJs and are expected targets for new antibody drugs. Herein, we review the literature on CLDNs, focusing on CLDN18 in GC.
| S-EPMC8773541 | biostudies-literature
Project description:Claudins are a large family of membrane proteins whose classic function is to regulate the permeability of tight junctions in epithelia. They are tetraspanins, with four alpha-helices crossing the membrane, two extracellular loops, a short cytoplasmic N-terminus and a longer and more variable C-terminus. The extracellular ends of the helices are known to undergo side-to-side (cis) interactions that allow the formation of claudin polymers in the plane of the membrane. The extracellular loops also engage in head-to-head (trans) interactions thought to mediate the formation of tight junctions. However, claudins are also present in intracellular structures, thought to be vesicles, with less well-characterized functions. Here, we briefly review our current understanding of claudin structure and function followed by an examination of changes in claudin mRNA and protein expression and localization through mammary gland development. Claudins-1, 3, 4, 7, and 8 are the five most prominent members of the claudin family in the mouse mammary gland, with varied abundance and intracellular localization during the different stages of post-pubertal development. Claudin-1 is clearly localized to tight junctions in mammary ducts in non-pregnant non-lactating animals. Cytoplasmic puncta that stain for claudin-7 are present throughout development. During pregnancy claudin-3 is localized both to the tight junction and basolaterally while claudin-4 is found only in sparse puncta. In the lactating mouse both claudin-3 and claudin-8 are localized at the tight junction where they may be important in forming the paracellular barrier. At involution and under challenge by lipopolysaccharide claudins -1, -3, and -4 are significantly upregulated. Claudin-3 is still colocalized with tight junction molecules but is also distributed through the cytoplasm as is claudin-4. These largely descriptive data provide the essential framework for future mechanistic studies of the function and regulation of mammary epithelial cell claudins.
| S-EPMC5488167 | biostudies-literature
Project description:Claudins, the major transmembrane proteins of tight junctions, are members of the tetraspanin superfamily of proteins that mediate cellular adhesion and migration. Their functional importance is demonstrated by mutations in claudin genes that eliminate tight junctions in myelin and the testis, abolish Mg(2+) resorption in the kidney, and cause autosomal recessive deafness. Here we report that two paralogs among 15 claudin genes in the zebrafish, Danio rerio, are expressed in the otic and lateral-line placodes at their earliest stages of development. Related claudins in amphibians and mammals are expressed in a similar manner in vertebrate primordia such as sensory placodes, branchial arches, and limb buds. We also show that the claudin gene family may have expanded along the chordate stem lineage from urochordates to gnathostomes, in parallel with the elaboration of vertebrate characters. We propose that tight junctions not only form barriers in mature epithelia, but also participate in vertebrate morphogenesis.
| S-EPMC56938 | biostudies-literature
Project description:The importance of the expression profile of claudins in the molecular classification of breast cancer (BC) is currently under investigation. Claudins, together with cadherins, serve an important role in the epithelial-mesenchymal transition and influence the chemosensitivity of cancer cells. Adjuvant chemotherapy is administered following surgical resection in selected cases of BC. Previous neoadjuvant chemotherapy may change the molecular profile of a tumour and subsequently also its chemosensitivity. In the current study, the expression of claudin-1, -3 and -4, E- and N-cadherin and the standard BC biomarkers [oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and marker of proliferation Ki-67 (Ki-67)] in formalin-fixed, paraffin-embedded sections from 62 patients with invasive BC was analysed using immunohistochemistry prior to and following neoadjuvant chemotherapy. The results revealed increased expression of claudin-1 (P=0.03) and decreased expression of claudin-3 (P=0.005), PR (P<0.001) and Ki-67 (P=0.01) following the neoadjuvant therapy. No significant changes in the expression of ER, claudin-4 or E- and N-cadherin were observed following therapy. Furthermore, an association between the expression of claudin-1 and the standard BC markers (P<0.05) was identified. A high expression of claudin-1 was more frequently observed in the triple-negative BC cohort than in the cohort with positive ER, PR and/or HER2 before (P=0.04) and after chemotherapy (P=0.02). The expression of N-cadherin was associated with the expression of ER, PR, HER2 and tumour grade (P<0.05). A positive association between the expression of claudin-3 and E-cadherin (P=0.005) was observed. No association was found between the expression of E- and N-cadherin. In conclusion, significant changes in the expression of claudin-1 and -3 but not in the expression of claudin-4, E- and N-cadherin were observed in samples taken from patients with BC following chemotherapy. These findings indicate that claudins-1 and -3 serve a role in the response of BC to chemotherapy.
| S-EPMC6755479 | biostudies-literature
Project description:Tight junctions (TJs) are large intercellular adhesion complexes that maintain cell polarity in normal epithelia and endothelia. Claudins are critical components of TJs, forming homo- and heteromeric interaction between adjacent cells, which have emerged as key functional modulators of carcinogenesis and metastasis. Numerous epithelial-derived cancers display altered claudin expression patterns, and these aberrantly expressed claudins have been shown to regulate cancer cell proliferation/growth, metabolism, metastasis and cell stemness. Certain claudins can now be used as biomarkers to predict patient prognosis in a variety of solid cancers. Our understanding of the distinct roles played by claudins during the cancer progression has progressed significantly over the last decade and claudins are now being investigated as possible diagnostic markers and therapeutic targets. In this review, we will summarize recent progress in the use of antibody-based or related strategies for targeting claudins in cancer treatment. We first describe pre-clinical studies that have facilitated the development of neutralizing antibodies and antibody-drug-conjugates targeting Claudins (Claudins-1, -3, -4, -6 and 18.2). Next, we summarize clinical trials assessing the efficacy of antibodies targeting Claudin-6 or Claudin-18.2. Finally, emerging strategies for targeting Claudins, including Chimeric Antigen Receptor (CAR)-T cell therapy and Bi-specific T cell engagers (BiTEs), are also discussed.
| S-EPMC10869466 | biostudies-literature
Project description:Increasing evidence has linked claudins to signal transduction and tumorigenesis. The expression of claudins is frequently dysregulated in the context of neoplastic transformation, suggesting their promise as biomarkers for diagnosis and prognosis or targets for treatment. Claudin binders (Clostridium perfringens enterotoxin and monoclonal antibody) have been tested in preclinical experiments, and some of them have progressed into clinical trials involving patients with certain cancers. However, the clinical development of many of these agents has not advanced to clinical applications. Herein, I review the current status of preclinical and clinical investigations of agents targeting claudins for diagnosis, prognosis and therapy. I also discuss the potential of combining claudin binders with other currently approved therapeutic agents.
| S-EPMC8332862 | biostudies-literature
Project description:Claudins are tight junction membrane proteins that regulate paracellular permeability of renal epithelia to small ions, solutes, and water. Claudins interact within the cell membrane and between neighboring cells to form tight junction strands and constitute both the paracellular barrier and the pore. The first extracellular domain of claudins is thought to be the pore-lining domain and contains the determinants of charge selectivity. Multiple claudins are expressed in different nephron segments; such differential expression likely determines the permeability properties of each segment. Recent evidence has identified claudin-2 as constituting the cation-reabsorptive pathway in the proximal tubule; claudin-14, -16, and -19 as forming a complex that regulates calcium transport in the thick ascending limb of the loop of Henle; and claudin-4, -7, and -8 as determinants of collecting duct chloride permeability. Mutations in claudin-16 and -19 cause familial hypercalciuric hypomagnesemia with nephrocalcinosis. The roles of other claudins in kidney diseases remain to be fully elucidated.
| S-EPMC3759403 | biostudies-literature
Project description:Claudins are tight-junction membrane proteins that function as both pores and barriers in the paracellular pathway in epithelial cells. In the kidney, claudins determine the permeability and selectivity of different nephron segments along the renal tubule. In the proximal tubule, claudins have a role in the bulk reabsorption of salt and water. In the thick ascending limb, claudins are important for the reabsorption of calcium and magnesium and are tightly regulated by the calcium-sensing receptor. In the distal nephron, claudins need to form cation barriers and chloride pores to facilitate electrogenic sodium reabsorption and potassium and acid secretion. Aldosterone and the with-no-lysine (WNK) proteins likely regulate claudins to fine-tune distal nephron salt transport. Genetic mutations in claudin-16 and -19 cause familial hypomagnesemic hypercalciuria with nephrocalcinosis, whereas polymorphisms in claudin-14 are associated with kidney stone risk. It is likely that additional roles for claudins in the pathogenesis of other types of kidney diseases have yet to be uncovered.
| S-EPMC4279745 | biostudies-literature
Project description:Tight junctions are the most apically localized part of the epithelial junctional complex. They regulate the permeability and polarity of cell layers and create compartments in cell membranes. Claudins are structural molecules of tight junctions. There are 27 claudins known, and expression of different claudins is responsible for changes in the electrolyte and solute permeability in cells layers. Studies have shown that claudins and tight junctions also protect multicellular organisms from infections and that some infectious agents may use claudins as targets to invade and weaken the host's defense. In neoplastic diseases, claudin expression may be up- or downregulated. Since their expression is associated with specific tumor types or with specific locations of tumors to a certain degree, they can, in a restricted sense, also be used as tumor markers. However, the regulation of claudin expression is complex involving growth factors and integrins, protein kinases, proto-oncogens and transcription factors. In this review, the significance of claudins is discussed in lung disease and development.
| S-EPMC3128860 | biostudies-literature
Project description:Purpose of reviewThe tight junction conductance made of the claudin-based paracellular channel is important in the regulation of calcium and magnesium reabsorption in the kidney. This review describes recent findings of the structure, the function, and the physiologic regulation of claudin-14, claudin-16, and claudin-19 channels that through protein interactions confer calcium and magnesium permeability to the tight junction.Recent findingsMutations in two tight junction genes - claudin-16 and claudin-19 - cause the inherited renal disorder familial hypomagnesemia with hypercalciuria and nephrocalcinosis. A recent genome-wide association study has identified claudin-14 as a major risk gene of hypercalciuric nephrolithiasis. The crystal structure of claudin-19 has recently been resolved allowing the reconstruction of a claudin assembly model from cis-dimers made of claudin-16 and claudin-19 interaction. MicroRNAs have been identified as novel regulators of the claudin-14 gene. The microRNA-claudin-14 operon is directly regulated by the Ca sensing receptor gene in response to hypercalcemia.SummaryThe paracellular pathway in the kidney is particularly important for mineral metabolism. Three claudin proteins - claudin-14, claudin-16, and claudin-19 - contribute to the structure and function of this paracellular pathway. Genetic mutations and gene expression changes in these claudins may lead to alteration of the paracellular permeability to calcium and magnesium, ultimately affecting renal mineral metabolism.
| S-EPMC4891285 | biostudies-literature