The claudin family of proteins in human malignancy: a clinical perspective

Abstract

Tight junctions, or zonula occludens, are the most apical component of the junctional complex and provide one form of cell–cell adhesion in epithelial and endothelial cells. Nearly 90% of malignant tumors are derived from the epithelium. Loss of cell–cell adhesion is one of the steps in the progression of cancer to metastasis. At least three main tight junction family proteins have been discovered: occludin, claudin, and junctional adhesion molecule (JAM). Claudins are the most important structural and functional components of tight junction integral membrane proteins, with at least 24 members in mammals. They are crucial for the paracellular flux of ions and small molecules. Overexpression or downregulation of claudins is frequently observed in epithelial-derived cancers. However, molecular mechanisms by which claudins affect tumorigenesis remain largely unknown. As the pivotal proteins in epithelial cells, altered expression and distribution of different claudins have been reported in a wide variety of human malignancies, including pancreatic, colonic, lung, ovarian, thyroid, prostate, esophageal, and breast cancers. In this review, we will give the readers an overall picture of the changes in claudin expression observed in various cancers and their mechanisms of regulation. Downregulation of claudins contributes to epithelial transformation by increasing the paracellular permeability of nutrients and growth factors to cancerous cells. In the cases of upregulation of claudin expression, the barrier function of the cancerous epithelia changes, as they often display a disorganized arrangement of tight junction strands with increased permeability to paracellular markers. Finally, we will summarize the literature suggesting that claudins may become useful biomarkers for cancer detection and diagnosis as well as possible therapeutic targets for cancer treatment.

The impact of CLAUDIN-1 on follicular thyroid carcinoma aggressiveness

“…Translocation of CLAUDIN-1 from the cell membrane to subcellular compartments has been described in different human tumours and has been associated with the tumourigenicity of cancer cells (Miwa et al 2001). In addition, loss of membranous tight junction proteins could negatively influence cell cohesion and/or cell differentiation (Ding et al 2013). Moreover, in colon cancer, nuclear CLAUDIN-1 localization has been linked to cellular and metastatic behaviour (Dhawan et al 2005).…”

Helicobacter pyloritargets cancer-associated apical-junctional constituents in gastroids and gastric epithelial cells

“…Claudin-7 is a member of a family of 24 transmembrane proteins, which are important constituents of tight junctions and which are the main determinants of tight junction barrier function. 14 Disruption of tight junction complexes is associated with a variety of human diseases, including cancers of the GI tract. 14 H. pylori adhere to gastric epithelial cells in close proximity to tight junctions and can alter localisation of the component proteins that constitute these complexes.…”

“…14 Disruption of tight junction complexes is associated with a variety of human diseases, including cancers of the GI tract. 14 H. pylori adhere to gastric epithelial cells in close proximity to tight junctions and can alter localisation of the component proteins that constitute these complexes. 1516 Altered expression of claudin-7 has been implicated in several types of human cancers, 14 and in a mouse model of intestinal claudin-7 deficiency, loss of claudin-7 leads to increased proliferation.…”

Diagnostic Usefulness of Claudin-3 and Claudin-4 for Immunocytochemical Differentiation between Metastatic Adenocarcinoma Cells and Reactive Mesothelial Cells in Effusion Cell Blocks

“…In most tissues, a single cell expresses more than 2 claudin species, in various homotypic and heterotypic combinations, to form tight junction strands [14]. As with the pivotal proteins in epithelial cells, altered expression and distribution of different claudins have been reported in a wide variety of human malignancies [15,16,17]. Although the exact roles of these proteins in tumorigenesis remain unclear, evidence suggests that they represent promising targets for cancer detection and diagnosis.…”