CD146 (cluster of differentiation 146) also known as the melanoma cell adhesion molecule (MCAM) or cell surface glycoprotein MUC18, is a 113kDa cell adhesion molecule currently used as a marker for endothelial cell lineage. In humans, the CD146 protein is encoded by the MCAMgene.[5]
Function
MCAM functions as a receptor for laminin alpha 4,[6] a matrix molecule that is broadly expressed within the vascular wall. Accordingly, MCAM is highly expressed by cells that are components of the blood vessel wall, including vascular endothelial cells, smooth muscle cells and pericytes. Its function is still poorly understood, but evidence points to it being part of the endothelial junction associated with the actin cytoskeleton. A member of the Immunoglobulin superfamily, it consists of five Ig domains, a transmembrane domain, and a cytoplasmic region. It is expressed on chicken embryonic spleen and thymus, activated human T cells, endothelial progenitors such as angioblasts and mesenchymal stem cells, and strongly expressed on blood vessel endothelium and smooth muscle.
Two isoforms exist (MCAM long (MCAM-1), and MCAM short, or MCAM-s) which differ in the length of their cytoplasmic domain. Activation of these isoforms seems to produce functional differences as well. Natural killer cells transfected with MCAM-1 demonstrate decreased rolling velocity and increased cell adhesion to an endothelial cell monolayer and increased microvilli formation while cells transfected with MCAM-s showed no change in adhesion characteristics. Since these characteristics are important in leukocyte extravasation, MCAM-1 may be an important part of the inflammatory response.
CD146 has been demonstrated to appear on a small subset of T and B lymphocytes in the peripheral blood of healthy individuals. The CD146+ T cells display an immunophenotype consistent with effector memory cells and have a distinct gene profile from the CD146- T cells.[7][8] CD146 T cells have been shown by Dagur and colleagues to produce IL-17.[9]
CD146 has been seen as a marker for mesenchymal stem cells isolated from multiple adult and fetal organs,[10] and its expression may be linked to multipotency; mesenchymal stem cells with greater differentiation potential express higher levels of CD146 on the cell surface.[11]
Normal melanocytes do not express MCAM and the expression of MCAM is first found in nevi and melanoma cells.[13] MCAM expression is positively correlated to melanoma progression at which the expression of MCAM is highest in metastatic melanoma cells. The significance of MCAM upregulation is evident in melanoma cells cultured in 3D skin reconstruct in which MCAM facilitates the migration of melanoma into the dermis. Without the expression of MCAM melanoma cells are controlled by keratinocytes in the epidermis that inhibit penetrance beyond the basement membrane. The control by keratinocytes are only achieved by E-cadherin expression on the surface of melanoma cells. Melanoma cells with functional E-cadherin on the surface can only exclusively grow in the epidermis as keratinocytes frequently downregulate the expression of MCAM on melanoma cells.[13]
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Wang N, Fan Y, Ni P, Wang F, Gao X, Xue Q, Tang L (2008). "High glucose effect on the role of CD146 in human proximal tubular epithelial cells in vitro". Journal of Nephrology. 21 (6): 931–40. PMID19034879.
Samuels TL, Handler E, Syring ML, Pajewski NM, Blumin JH, Kerschner JE, Johnston N (September 2008). "Mucin gene expression in human laryngeal epithelia: effect of laryngopharyngeal reflux". The Annals of Otology, Rhinology, and Laryngology. 117 (9): 688–95. doi:10.1177/000348940811700911. PMID18834073. S2CID23385606.
Fritzsche FR, Wassermann K, Rabien A, Schicktanz H, Dankof A, Loening SA, et al. (August 2008). "CD146 protein in prostate cancer: revisited with two different antibodies". Pathology. 40 (5): 457–64. doi:10.1080/00313020802197996. PMID18604730. S2CID205448423.
Chen W, Zhang HL, Jiang YG, Li JH, Liu BL, Sun MY (February 2009). "Inhibition of CD146 gene expression via RNA interference reduces in vitro perineural invasion on ACC-M cell". Journal of Oral Pathology & Medicine. 38 (2): 198–205. doi:10.1111/j.1600-0714.2008.00706.x. PMID19200179.
Malyszko J, Malyszko JS, Kozminski P, Pawlak K, Mysliwiec M (July 2008). "Adipokines, linking adipocytes and vascular function in hemodialyzed patients, may also be possibly related to CD146, a novel adhesion molecule". Clinical and Applied Thrombosis/Hemostasis. 14 (3): 338–45. doi:10.1177/1076029607305083. PMID18160586. S2CID43210730.
Zheng C, Qiu Y, Zeng Q, Zhang Y, Lu D, Yang D, et al. (November 2009). "Endothelial CD146 is required for in vitro tumor-induced angiogenesis: the role of a disulfide bond in signaling and dimerization". The International Journal of Biochemistry & Cell Biology. 41 (11): 2163–72. doi:10.1016/j.biocel.2009.03.014. PMID19782948.
Saito O, Saito T, Okuda K, Okuda K, Kotoda A, Akimoto T, et al. (February 2008). "Serum adiponectin and markers of endothelial injury in hemodialysis patients with arteriosclerosis obliterans". Clinical and Experimental Nephrology. 12 (1): 58–64. doi:10.1007/s10157-007-0012-7. PMID18175063. S2CID34180131.
