CD146 explained

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 MCAM gene.^[1]

Function

MCAM functions as a receptor for laminin alpha 4,^[2] 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.^{[3] [4]} CD146 T cells have been shown by Dagur and colleagues to produce IL-17.^[5]

CD146 has been seen as a marker for mesenchymal stem cells isolated from multiple adult and fetal organs,^[6] and its expression may be linked to multipotency; mesenchymal stem cells with greater differentiation potential express higher levels of CD146 on the cell surface.^[7]

Relevance in cancer

MCAM inhibits breast cancer progression.^[8]

Normal melanocytes do not express MCAM and the expression of MCAM is first found in nevi and melanoma cells.^[9] 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.

Further reading

• Wang Z, Xu Q, Zhang N, Du X, Xu G, Yan X . CD146, from a melanoma cell adhesion molecule to a signaling receptor . Signal Transduction and Targeted Therapy . 5 . 1 . 148 . August 2020 . 32782280 . 7421905 . 10.1038/s41392-020-00259-8 .
• Guezguez B, Vigneron P, Lamerant N, Kieda C, Jaffredo T, Dunon D . Dual role of melanoma cell adhesion molecule (MCAM)/CD146 in lymphocyte endothelium interaction: MCAM/CD146 promotes rolling via microvilli induction in lymphocyte and is an endothelial adhesion receptor . Journal of Immunology . 179 . 10 . 6673–85 . November 2007 . 17982057 . 10.4049/jimmunol.179.10.6673 . free .
• Shih IM . The role of CD146 (Mel-CAM) in biology and pathology . The Journal of Pathology . 189 . 1 . 4–11 . September 1999 . 10451481 . 10.1002/(SICI)1096-9896(199909)189:1<4::AID-PATH332>3.0.CO;2-P . 43326956 . free .
• Staquicini FI, Tandle A, Libutti SK, Sun J, Zigler M, Bar-Eli M, Aliperti F, Pérez EC, Gershenwald JE, Mariano M, Pasqualini R, Arap W, Lopes JD . 6 . A subset of host B lymphocytes controls melanoma metastasis through a melanoma cell adhesion molecule/MUC18-dependent interaction: evidence from mice and humans . Cancer Research . 68 . 20 . 8419–28 . October 2008 . 18922915 . 2718575 . 10.1158/0008-5472.CAN-08-1242 .
• Johnson JP, Rothbächer U, Sers C . The progression associated antigen MUC18: a unique member of the immunoglobulin supergene family . Melanoma Research . 3 . 5 . 337–40 . October 1993 . 8292890 . 10.1097/00008390-199310000-00006 . 43280514 .
• McGary EC, Lev DC, Bar-Eli M . Cellular adhesion pathways and metastatic potential of human melanoma . Cancer Biology & Therapy . 1 . 5 . 459–65 . 2002 . 12496470 . 10.4161/cbt.1.5.158 . free .
• Barbe L, Lundberg E, Oksvold P, Stenius A, Lewin E, Björling E, Asplund A, Pontén F, Brismar H, Uhlén M, Andersson-Svahn H . 6 . Toward a confocal subcellular atlas of the human proteome . Molecular & Cellular Proteomics . 7 . 3 . 499–508 . March 2008 . 18029348 . 10.1074/mcp.M700325-MCP200 . free .
• Wang N, Fan Y, Ni P, Wang F, Gao X, Xue Q, Tang L . High glucose effect on the role of CD146 in human proximal tubular epithelial cells in vitro . Journal of Nephrology . 21 . 6 . 931–40 . 2008 . 19034879 .
• Bidlingmaier S, He J, Wang Y, An F, Feng J, Barbone D, Gao D, Franc B, Broaddus VC, Liu B . 6 . Identification of MCAM/CD146 as the target antigen of a human monoclonal antibody that recognizes both epithelioid and sarcomatoid types of mesothelioma . Cancer Research . 69 . 4 . 1570–7 . February 2009 . 19221091 . 2752656 . 10.1158/0008-5472.CAN-08-1363 .
• Russell KC, Phinney DG, Lacey MR, Barrilleaux BL, Meyertholen KE, O'Connor KC . In vitro high-capacity assay to quantify the clonal heterogeneity in trilineage potential of mesenchymal stem cells reveals a complex hierarchy of lineage commitment . Stem Cells . 28 . 4 . 788–98 . April 2010 . 20127798 . 10.1002/stem.312 . 45009922 . free .
• Tripodo C, Di Bernardo A, Ternullo MP, Guarnotta C, Porcasi R, Ingrao S, Gianelli U, Boveri E, Iannitto E, Franco G, Florena AM . 6 . CD146(+) bone marrow osteoprogenitors increase in the advanced stages of primary myelofibrosis . Haematologica . 94 . 1 . 127–30 . January 2009 . 19029148 . 2625423 . 10.3324/haematol.13598 .
• Samuels TL, Handler E, Syring ML, Pajewski NM, Blumin JH, Kerschner JE, Johnston N . Mucin gene expression in human laryngeal epithelia: effect of laryngopharyngeal reflux . The Annals of Otology, Rhinology, and Laryngology . 117 . 9 . 688–95 . September 2008 . 18834073 . 10.1177/000348940811700911 . 23385606 .
• Bardin N, Blot-Chabaud M, Despoix N, Kebir A, Harhouri K, Arsanto JP, Espinosa L, Perrin P, Robert S, Vely F, Sabatier F, Le Bivic A, Kaplanski G, Sampol J, Dignat-George F . 6 . CD146 and its soluble form regulate monocyte transendothelial migration . Arteriosclerosis, Thrombosis, and Vascular Biology . 29 . 5 . 746–53 . May 2009 . 19229070 . 10.1161/ATVBAHA.108.183251 . free .
• Fritzsche FR, Wassermann K, Rabien A, Schicktanz H, Dankof A, Loening SA, Dietel M, Jung K, Kristiansen G . 6 . CD146 protein in prostate cancer: revisited with two different antibodies . Pathology . 40 . 5 . 457–64 . August 2008 . 18604730 . 10.1080/00313020802197996 . 205448423 .
• Melnikova VO, Balasubramanian K, Villares GJ, Dobroff AS, Zigler M, Wang H, Petersson F, Price JE, Schroit A, Prieto VG, Hung MC, Bar-Eli M . 6 . Crosstalk between protease-activated receptor 1 and platelet-activating factor receptor regulates melanoma cell adhesion molecule (MCAM/MUC18) expression and melanoma metastasis . The Journal of Biological Chemistry . 284 . 42 . 28845–55 . October 2009 . 19703903 . 2781430 . 10.1074/jbc.M109.042150 . free .
• Chen W, Zhang HL, Jiang YG, Li JH, Liu BL, Sun MY . 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 . February 2009 . 19200179 . 10.1111/j.1600-0714.2008.00706.x .
• Zabouo G, Imbert AM, Jacquemier J, Finetti P, Moreau T, Esterni B, Birnbaum D, Bertucci F, Chabannon C . 6 . CD146 expression is associated with a poor prognosis in human breast tumors and with enhanced motility in breast cancer cell lines . Breast Cancer Research . 11 . 1 . R1 . 2009 . 19123925 . 2687703 . 10.1186/bcr2215 . free .
• Schwab KE, Gargett CE . Co-expression of two perivascular cell markers isolates mesenchymal stem-like cells from human endometrium . Human Reproduction . 22 . 11 . 2903–11 . November 2007 . 17872908 . 10.1093/humrep/dem265 . free .
• Malyszko J, Malyszko JS, Kozminski P, Pawlak K, Mysliwiec M . 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 . July 2008 . 18160586 . 10.1177/1076029607305083 . 43210730 .
• Zheng C, Qiu Y, Zeng Q, Zhang Y, Lu D, Yang D, Feng J, Yan X . 6 . 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 . November 2009 . 19782948 . 10.1016/j.biocel.2009.03.014 .
• Saito O, Saito T, Okuda K, Okuda K, Kotoda A, Akimoto T, Ando Y, Muto S, Ishikawa SE, Kusano E . 6 . Serum adiponectin and markers of endothelial injury in hemodialysis patients with arteriosclerosis obliterans . Clinical and Experimental Nephrology . 12 . 1 . 58–64 . February 2008 . 18175063 . 10.1007/s10157-007-0012-7 . 34180131 .

Notes and References

1. Kuske MD, Johnson JP . Assignment of the human melanoma cell adhesion molecule gene (MCAM) to chromosome 11 band q23.3 by radiation hybrid mapping . Cytogenetics and Cell Genetics . 87 . 3–4 . 258 . 1999 . 10702685 . 10.1159/000015439 . 37508075 .
2. Flanagan K, Fitzgerald K, Baker J, Regnstrom K, Gardai S, Bard F, Mocci S, Seto P, You M, Larochelle C, Prat A, Chow S, Li L, Vandevert C, Zago W, Lorenzana C, Nishioka C, Hoffman J, Botelho R, Willits C, Tanaka K, Johnston J, Yednock T . 6 . Laminin-411 is a vascular ligand for MCAM and facilitates TH17 cell entry into the CNS . PLOS ONE . 7 . 7 . e40443 . 2012 . 22792325 . 3391262 . 10.1371/journal.pone.0040443 . 2012PLoSO...740443F . free .
3. Elshal MF, Khan SS, Takahashi Y, Solomon MA, McCoy JP . CD146 (Mel-CAM), an adhesion marker of endothelial cells, is a novel marker of lymphocyte subset activation in normal peripheral blood . Blood . 106 . 8 . 2923–4 . October 2005 . 16204154 . 10.1182/blood-2005-06-2307 . free .
4. Elshal MF, Khan SS, Raghavachari N, Takahashi Y, Barb J, Bailey JJ, Munson PJ, Solomon MA, Danner RL, McCoy JP . 6 . A unique population of effector memory lymphocytes identified by CD146 having a distinct immunophenotypic and genomic profile . BMC Immunology . 8 . 29 . November 2007 . 17999761 . 2248207 . 10.1186/1471-2172-8-29 . free .
5. Dagur PK, Biancotto A, Wei L, Sen HN, Yao M, Strober W, Nussenblatt RB, McCoy JP . 6 . MCAM-expressing CD4(+) T cells in peripheral blood secrete IL-17A and are significantly elevated in inflammatory autoimmune diseases . Journal of Autoimmunity . 37 . 4 . 319–27 . December 2011 . 21959269 . 3223259 . 10.1016/j.jaut.2011.09.003 .
6. Covas DT, Panepucci RA, Fontes AM, Silva WA, Orellana MD, Freitas MC, Neder L, Santos AR, Peres LC, Jamur MC, Zago MA . 6 . Multipotent mesenchymal stromal cells obtained from diverse human tissues share functional properties and gene-expression profile with CD146+ perivascular cells and fibroblasts . Experimental Hematology . 36 . 5 . 642–54 . May 2008 . 18295964 . 10.1016/j.exphem.2007.12.015 . free .
7. Russell KC, Phinney DG, Lacey MR, Barrilleaux BL, Meyertholen KE, O'Connor KC . In vitro high-capacity assay to quantify the clonal heterogeneity in trilineage potential of mesenchymal stem cells reveals a complex hierarchy of lineage commitment . Stem Cells . 28 . 4 . 788–98 . April 2010 . 20127798 . 10.1002/stem.312 . 45009922 . free .
8. Ouhtit A, Gaur RL, Abd Elmageed ZY, Fernando A, Thouta R, Trappey AK, Abdraboh ME, El-Sayyad HI, Rao P, Raj MG . 6 . Towards understanding the mode of action of the multifaceted cell adhesion receptor CD146 . Biochimica et Biophysica Acta (BBA) - Reviews on Cancer . 1795 . 2 . 130–6 . April 2009 . 19356677 . 10.1016/j.bbcan.2009.01.002 .
9. Haass NK, Smalley KS, Li L, Herlyn M . Adhesion, migration and communication in melanocytes and melanoma . Pigment Cell Research . 18 . 3 . 150–9 . June 2005 . 15892711 . 10.1111/j.1600-0749.2005.00235.x . free .