Recent Research Progress
Cadherin-11 (Cad-11, also known as OB cadherin or CDH11) is a member of the cadherin superfamily, a group of transmembrane proteins that are primarily located at the adhesion junction and mediate homosexual cell-to-cell adhesion. The intracellular domain includes binding sites for signaling molecules, such as b-catenin. Cadherin-11 is also involved in many other biological functions, including cytoskeletal organization, tissue morphogenesis, cell migration and invasion. In particular, Cadherin-11 plays an important role in epithelial-to-mesenchymal transition, which represents an inflammation-induced response that has a fundamental role in the progression from chronic inflammation to cancer. The regulation of Cadherin-11 expression is associated with many pathological processes such as inflammation, fibrosis and cancer.
Cadherin-11 and inflammation disease
Cadherin-11 has been identified as a key regulator of synovial structure, mediating contact between fibroblast-like synoviocytes and lining tissue. The central role of Cadherin-11 has also been proposed in the formation of the rheumatoid pannus. The therapeutic targeting of Cadherin-11 leads to amelioration of autoimmune experimental arthritis, as well as of experimental fibrosis. Cadherin-11 expression is up-regulated in the synovium of patients with chronic inflammatory arthritis, whereas detection of Cadherin-11 messenger RNA (mRNA) transcripts in peripheral blood is associated with a more severe disease phenotype in the two prototype conditions of chronic joint inflammation and fibrosis, namely, rheumatoid arthritis and systemic sclerosis. In addition, studies have found that overexpression of Cadherin-11 in osteoarthritis (OA) is positively correlated with synovitis severity, and can be driven by proinflammatory cytokines on OA Fibroblast-like Synoviocytes (FLS); Cadherin-11 increases migratory or invasive capacity and matrix metalloproteinase-2 (MMP-2) production of FLS of osteoarthritis. In summary, current data suggest that Cadherin-11 is a therapeutic target for possible inflammatory diseases.
Cadherin-11 and cancer
Cadherin-11 is normally expressed in mesenchymal cells and promotes adhesion between these cells. Cadherin-11 expression is associated with osteoblast differentiation and promotes cartilage osteogenesis and inhibits adipogenesis. Consistent with carcinogenesis, Cadherin-11 promotes prostate cancer cell invasion and bone metastasis. Cadherin-11 is overexpressed in neck squamous cell carcinoma (HNSCC) compared to normal specimens. In human chronic pancreatitis and pancreatic cancer tissues, Cadherin-11 expression is significantly increased in pancreatic stellate cells (PSC) and pancreatic cancer cells. The mesenchymal marker Cadherin-11 has been identified as a potential mediator of neurotrophin receptor p75 (p75NTR)-induced migration of glioblastoma cells. There is a significant difference in mRNA transcription and protein expression of Cadherin-11 in malignant breast tissue compared with benign and/or healthy tissues. Cadherin-11 may be a potential therapeutic target for breast cancer.
Cadherin-11 and other disease
Cadherin-11, a marker and functional regulator of fibroblasts, has been shown to regulate macrophage phenotype and glucose intolerance in diet-induced obesity by fibroblast stromal cells in adipose tissue. Recent studies have found that Cadherin-11-deficient mice had increased Interleukin 33 (IL-33)–producing PDGFRα+ fibroblasts, increased innate lymphoid type 2 cells (ILC2s) and IL-13, and associated expansion of M2 (anti-inflammatory phenotypes) macrophages. Decreased adipose tissue inflammation in Cadherin-11 deficient mice was associated with improved glycemic control and metabolic syndrome. These findings strongly point to the importance of mesenchymal stromal cells and their chance to treat adipose tissue inflammation, diabetes and metabolic syndrome by targeting them with Cadherin-11. In addition, the study found that Cadherin-11 is downstream of NOTCH1 receptor dysfunction and may be a marker of hereditary and idiopathic calcific aortic valve disease (CAVD).
In conclusion, Cadherin-11 plays a major role in the pathogenesis of many inflammatory diseases and cancers. Therefore, further study of the function of Cadherin-11 will provide new potential therapeutic targets for the diagnosis and treatment of related inflammatory diseases and cancer.
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