Context-Dependent Roles of Claudins in Tumorigenesis

Li, Jian

doi:10.3389/fonc.2021.676781

Cited by 25 publications

(27 citation statements)

References 179 publications

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“…The tubular arrangement of tumor epithelial cells is associated with Claudins because Claudin deletion mutants lead to tumors with decreased tubular arrangement [ 12 ]. Claudins thus alter cellular proliferation [ 12 , 13 ]. Due to the important roles Claudins play in hindering the metastasis and proliferation of cancer cells, Claudins are plausible targets for therapeutic intervention.…”

Section: Molecular Targets Of Cpe In the Human Bodymentioning

confidence: 99%

“…Claudin expression levels vary with tumor types, tumor aggression, and invasion potential [ 13 ] ( Figure 3 ). Deletion mutations of Claudins are crucial in the progression and invasive potential of tumors as Claudins regulate the permeability of the epithelial membrane to the flux of ions and small molecules in order to maintain epithelial polarity and homeostasis [ 12 , 25 ].…”

Section: Application Of Cpe and Claudin-4 Interactions In Treatment O...mentioning

confidence: 99%

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Application of C-Terminal Clostridium Perfringens Enterotoxin in Treatment of Brain Metastasis from Breast Cancer

Banga

Odiase

Rachakonda

et al. 2022

Cancers

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Claudin-4 is part of the Claudin family of transmembrane tight junction (TJ) proteins found in almost all tissues and, together with adherens junctions and desmosomes, forms epithelial and endothelial junctional complexes. Although the distribution of Claudin-4 occurs in many cell types, the level of expression is cell-specific. Claudin proteins regulate cell proliferation and differentiation by binding cell-signaling ligands, and its expression is upregulated in several cancers. As a result, alterations in Claudin expression patterns or distribution are vital in the pathology of cancer. Profiling the genetic expression of Claudin-4 showed that Claudin-4 is also a receptor for the clostridium perfringens enterotoxin (CPE) and that Claudin-4 has a high sequence similarity with CPE’s high-affinity receptor. CPE is cytolytic due to its ability to form pores in cellular membranes, and CPE treatment in breast cancer cells have shown promising results due to the high expression of Claudin-4. The C-terminal fragment of CPE (c-CPE) provides a less toxic alternative for drug delivery into breast cancer cells, particularly metastatic tumors in the brain, especially as Claudin-4 expression in the central nervous system (CNS) is low. Therefore, c-CPE provides a unique avenue for the treatment of breast–brain metastatic tumors.

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Section: Molecular Targets Of Cpe In the Human Bodymentioning

confidence: 99%

Section: Application Of Cpe and Claudin-4 Interactions In Treatment O...mentioning

confidence: 99%

Application of C-Terminal Clostridium Perfringens Enterotoxin in Treatment of Brain Metastasis from Breast Cancer

Banga

Odiase

Rachakonda

et al. 2022

Cancers

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“…CLDNs are expressed in distinct patterns in different tissues and cells. Furthermore, CLDNs are useful cancer biomarkers, as they are frequently upregulated and are associated with malignant traits of cancers, such as invasion, migration, metastasis and chemoresistance (13,14). their genes are located adjacent to each other on the human genome.…”

Section: Introductionmentioning

confidence: 99%

Claudin‑9 is a novel prognostic biomarker for endometrial cancer

et al. 2022

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The tight-junction protein claudin-9 (CLDN9) is barely distributed in normal adult tissues but is ectopically expressed in various cancer types. Although multiple databases indicated upregulation of CLDN9 in endometrial cancers at the mRNA level, its protein expression and biological roles remain obscure. In the present study, the prognostic significance of CLDN9 expression in endometrial cancer was evaluated by immunohistochemical staining and semi-quantification using formalin-fixed paraffin-embedded specimens obtained from 248 endometrial carcinoma cases. A total of 43 cases (17.3%) had high CLDN9 expression, whereas 205 cases (82.7%) exhibited low CLDN9 expression. The 5-year disease-specific survival rates in the high and low CLDN9 expression groups were 62.8 and 87.8% (P<0.001), respectively. In addition, multivariate analysis revealed that high CLDN9 expression was an independent prognostic factor (hazard ratio, 4.99; 95% CI, 1.96-12.70; P<0.001). Furthermore, CLDN9 expression was significantly correlated with the expression of CLDN6 (P<0.001), which is the closest CLDN member to CLDN9 and a poor prognostic factor for endometrial carcinoma. The 5-year disease-specific survival rate of cases with CLDN6-high/CLDN9-high, CLDN6-high/CLDN9-low and CLDN6-low/CLDN9-high status was 30.0, 37.5 and 72.7%, respectively, whereas that of CLDN6-low/CLDN9-low was 89.8% (P=0.004). In conclusion, aberrant CLDN9 expression is a predictor of poor prognosis for endometrial cancer and may be utilized in combination with CLDN6 to achieve higher sensitivity. Recent studies by our group demonstrated that aberrant CLDN6 expression is a biomarker for poor prognosis in endometrial cancer, and that abnormal CLDN6 signaling enhances malignant behaviors by AKT-dependent phosphorylation of estrogen receptor-α (ERα) through the Src-family kinases (SFK)/PI3K/AKT signaling pathway (15-17). Among CLDN subtypes, CLDN9 is the closest member to CLDN6 (18) and

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“…JAM proteins form homotypic and heterotypic interaction among the same family members and may influence other members of the TJ [ 7 , 8 ]. Contrary to the effects of other TJ components [ 9 ], JAMs are responsible for increased proliferation when downregulated [ 10 ]. JAM-A upregulation has been associated with endothelial to mesenchymal transition (EMT) [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Using the Power of Junctional Adhesion Molecules Combined with the Target of CAR-T to Inhibit Cancer Proliferation, Metastasis and Eradicate Tumors

Mendoza

Mizrachi

2022

Biomedicines

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Decades of evidence suggest that alterations in the adhesion properties of neoplastic cells endow them with an invasive and migratory phenotype. Tight junctions (TJs) are present in endothelial and epithelial cells. Tumors arise from such tissues, thus, the role of TJ proteins in the tumor microenvironment is highly relevant. In the TJ, junctional adhesion molecules (JAM) play a key role in assembly of the TJ and control of cell–cell adhesion. Reprogramming of immune cells using chimeric antigen receptors (CAR) to allow for target recognition and eradication of tumors is an FDA approved therapy. The best-studied CAR-T cells recognize CD19, a B-cell surface molecule. CD19 is not a unique marker for tumors, liquid or solid. To address this limitation, we developed a biologic containing three domains: (1) pH-low-insertion peptide (pHLIP), which recognizes the low pH of the cancer cells, leading to the insertion of the peptide into the plasma membrane. (2) An extracellular domain of JAM proteins that fosters cell–cell interactions. (3) CD19 to be targeted by CAR-T cells. Our modular design only targets cancer cells and when coupled with anti-CD19 CAR-T cells, it decreases proliferation and metastasis in at least two cancer cell lines.

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Context-Dependent Roles of Claudins in Tumorigenesis

Cited by 25 publications

References 179 publications

Application of C-Terminal Clostridium Perfringens Enterotoxin in Treatment of Brain Metastasis from Breast Cancer

Application of C-Terminal Clostridium Perfringens Enterotoxin in Treatment of Brain Metastasis from Breast Cancer

Claudin‑9 is a novel prognostic biomarker for endometrial cancer

Using the Power of Junctional Adhesion Molecules Combined with the Target of CAR-T to Inhibit Cancer Proliferation, Metastasis and Eradicate Tumors

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