Skip to main content
SpringerLink
Log in

CD146, a therapeutic target involved in cell plasticity

  • Review
  • Published:
Science China Life Sciences Aims and scope Submit manuscript

Abstract

Since its identification as a marker for advanced melanoma in the 1980s, CD146 has been found to have multiple functions in both physiological and pathological processes, including embryonic development, tissue repair and regeneration, tumor progression, fibrosis disease, and inflammations. Subsequent research has revealed that CD146 is involved in various signaling pathways as a receptor or co-receptor in these processes. This correlation between CD146 and multiple diseases has sparked interest in its potential applications in diagnosis, prognosis, and targeted therapy. To better comprehend the versatile roles of CD146, we have summarized its research history and synthesized findings from numerous reports, proposing that cell plasticity serves as the underlying mechanism through which CD146 contributes to development, regeneration, and various diseases. Targeting CD146 would consequently halt cell state shifting during the onset and progression of these related diseases. Therefore, the development of therapy targeting CD146 holds significant practical value.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abed, A., Leroyer, A.S., Kavvadas, P., Authier, F., Bachelier, R., Foucault-Bertaud, A., Bardin, N., Cohen, C.D., Lindenmeyer, M.T., Genest, M., et al. (2021). Endothelial-specific deletion of CD146 protects against experimental glomerulonephritis in mice. Hypertension 77, 1260–1272.

    Article  CAS  PubMed  Google Scholar 

  • Abu El-Asrar, A.M., Nawaz, M.I., Ahmad, A., Siddiquei, M.M., Allegaert, E., Gikandi, P.W., De Hertogh, G., and Opdenakker, G. (2021). CD146/soluble CD146 pathway is a novel biomarker of angiogenesis and inflammation in proliferative diabetic retinopathy. Invest Ophthalmol Vis Sci 62, 32.

    Article  PubMed  PubMed Central  Google Scholar 

  • Akbar, M., McLean, M., Garcia-Melchor, E., Crowe, L.A., McMillan, P., Fazzi, U.G., Martin, D., Arthur, A., Reilly, J.H., McInnes, I.B., et al. (2019). Fibroblast activation and inflammation in frozen shoulder. PLoS ONE 14, e0215301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baecher-Allan, C., Kaskow, B.J., and Weiner, H.L. (2018). Multiple sclerosis: mechanisms and immunotherapy. Neuron 97, 742–768.

    Article  CAS  PubMed  Google Scholar 

  • Bal, S.M., Golebski, K., and Spits, H. (2020). Plasticity of innate lymphoid cell subsets. Nat Rev Immunol 20, 552–565.

    Article  CAS  PubMed  Google Scholar 

  • Bardin, N., Blot-Chabaud, M., Despoix, N., Kebir, A., Harhouri, K., Arsanto, J.P., Espinosa, L., Perrin, P., Robert, S., Vely, F., et al. (2009). CD146 and its soluble form regulate monocyte transendothelial migration. Arterioscler Thromb Vasc Biol 29, 746–753.

    Article  CAS  PubMed  Google Scholar 

  • Biswas, S.K., and Mantovani, A. (2010). Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol 11, 889–896.

    Article  CAS  PubMed  Google Scholar 

  • Bosserhoff, A.K., Ellmann, L., and Kuphal, S. (2011). Melanoblasts in culture as an in vitro system to determine molecular changes in melanoma. Exp Dermatol 20, 435–440.

    Article  CAS  PubMed  Google Scholar 

  • Bouvier, S., Kaspi, E., Joshkon, A., Paulmyer-Lacroix, O., Piercecchi-Marti, M.D., Sharma, A., Leroyer, A.S., Bertaud, A., Gris, J.C., Dignat-George, F., et al. (2021). The role of the adhesion receptor CD146 and its soluble form in human embryo implantation and pregnancy. Front Immunol 12, 711394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bouvier, S., Paulmyer-Lacroix, O., Molinari, N., Bertaud, A., Paci, M., Leroyer, A., Robert, S., Dignat George, F., Blot-Chabaud, M., and Bardin, N. (2017). Soluble CD146, an innovative and non-invasive biomarker of embryo selection for in vitro fertilization. PLOS ONE 12, e0173724.

    Article  PubMed  PubMed Central  Google Scholar 

  • Brabletz, S., Schuhwerk, H., Brabletz, T., and Stemmler, M.P. (2021). Dynamic EMT: a multi-tool for tumor progression. EMBO J 40, e108647.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brechbuhl, H.M., Barrett, A.S., Kopin, E., Hagen, J.C., Han, A.L., Gillen, A.E., Finlay-Schultz, J., Cittelly, D.M., Owens, P., Horwitz, K.B., et al. (2020). Fibroblast subtypes define a metastatic matrisome in breast cancer. JCI Insight 5, e130751.

    Article  PubMed  PubMed Central  Google Scholar 

  • Brechbuhl, H.M., Finlay-Schultz, J., Yamamoto, T.M., Gillen, A.E., Cittelly, D.M., Tan, A.C., Sams, S.B., Pillai, M.M., Elias, A.D., Robinson, W.A., et al. (2017). Fibroblast subtypes regulate responsiveness of luminal breast cancer to estrogen. Clin Cancer Res 23, 1710–1721.

    Article  CAS  PubMed  Google Scholar 

  • Breuer, J., Korpos, E., Hannocks, M.J., Schneider-Hohendorf, T., Song, J., Zondler, L., Herich, S., Flanagan, K., Korn, T., Zarbock, A., et al. (2018). Blockade of MCAM/ CD146 impedes CNS infiltration of T cells over the choroid plexus. J Neuroinflamm 15, 236.

    Article  Google Scholar 

  • Brucklacher-Waldert, V., Stuerner, K., Kolster, M., Wolthausen, J., and Tolosa, E. (2009). Phenotypical and functional characterization of T helper 17 cells in multiple sclerosis. Brain 132, 3329–3341.

    Article  PubMed  Google Scholar 

  • Bu, P., Gao, L., Zhuang, J., Feng, J., Yang, D., and Yan, X. (2006). Anti-CD146 monoclonal antibody AA98 inhibits angiogenesis via suppression of nuclear factor-κB activation. Mol Cancer Ther 5, 2872–2878.

    Article  CAS  PubMed  Google Scholar 

  • Canse, C., Yildirim, E., and Yaba, A. (2023). Overview of junctional complexes during mammalian early embryonic development. Front Endocrinol (Lausanne) 14, 1150017.

    Article  PubMed  Google Scholar 

  • Caplan, A.I. (2007). Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. J Cell Physiol 213, 341–347.

    Article  CAS  Google Scholar 

  • Castriconi, R., Dondero, A., Negri, F., Bellora, F., Nozza, P., Carnemolla, B., Raso, A., Moretta, L., Moretta, A., and Bottino, C. (2007). Both CD133+ and CD133− medulloblastoma cell lines express ligands for triggering NK receptors and are susceptible to NK-mediated cytotoxicity. Eur J Immunol 37, 3190–3196.

    Article  CAS  PubMed  Google Scholar 

  • Chan, B., Sinha, S., Cho, D., Ramchandran, R., and Sukhatme, V.P. (2005). Critical roles of CD146 in zebrafish vascular development. Dev Dyn 232, 232–244.

    Article  CAS  PubMed  Google Scholar 

  • Chang, Z., Xiao, Q., Feng, Q., and Yang, Z. (2010). PKB/Akt signaling in heart development and disease. Front Biosci E2, 1485–1491.

    Article  CAS  Google Scholar 

  • Charabati, M., Zandee, S., Fournier, A.P., Tastet, O., Thai, K., Zaminpeyma, R., Lécuyer, M.A., Bourbonnière, L., Larouche, S., Klement, W., et al. (2023). MCAM+ brain endothelial cells contribute to neuroinflammation by recruiting pathogenic CD4+ T lymphocytes. Brain 146, 1483–1495.

    Article  PubMed  Google Scholar 

  • Chaudhari-Kank, M.S., Zaveri, K., Antia, V., and Hinduja, I. (2018). Comparison of CD9 & CD146 markers in endometrial stromal cells of fertile & infertile females. Ind J Med Res 147, 552–559.

    Article  CAS  Google Scholar 

  • Chen, J., Luo, Y., Huang, H., Wu, S., Feng, J., Zhang, J., and Yan, X. (2018). CD146 is essential for PDGFRβ-induced pericyte recruitment. Protein Cell 9, 743–747.

    Article  CAS  PubMed  Google Scholar 

  • Chen, J., Luo, Y., Hui, H., Cai, T., Huang, H., Yang, F., Feng, J., Zhang, J., and Yan, X. (2017). CD146 coordinates brain endothelial cell-pericyte communication for blood-brain barrier development. Proc Natl Acad Sci USA 114, E7622–E7631.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen, K., Ding, A., Ding, Y., and Ghanekar, A. (2016). High-throughput flow cytometry screening of human hepatocellular carcinoma reveals CD146 to be a novel marker of tumor-initiating cells. Biochem Biophys Rep 8, 107–113.

    PubMed  PubMed Central  Google Scholar 

  • Chen, M. K., and Hung, M. C. (2016). Regulation of therapeutic resistance in cancers by receptor tyrosine kinases. Am J Cancer Res 2016, 6: 827–842.

    PubMed  PubMed Central  Google Scholar 

  • Chen, X., Huan, H., Liu, C., Luo, Y., Shen, J., Zhuo, Y., Zhang, Z., and Qian, C. (2019). Deacetylation of β-catenin by SIRT1 regulates self-renewal and oncogenesis of liver cancer stem cells. Cancer Lett 463, 1–10.

    Article  CAS  PubMed  Google Scholar 

  • Chen, X., Yan, H., Liu, D., Xu, Q., Duan, H., Feng, J., Yan, X., and Xie, C. (2021). Structure basis for AA98 inhibition on the activation of endothelial cells mediated by CD146. iScience 24, 102417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dagur, P.K., Biancotto, A., Wei, L., Nida Sen, H., Yao, M., Strober, W., Nussenblatt, R. B., and Philip McCoy Jr., J. (2011). MCAM-expressing CD4+ T cells in peripheral blood secrete IL-17A and are significantly elevated in inflammatory autoimmune diseases. J Autoimmun 37, 319–327.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dagur, P.K., and McCoy Jr., J.P. (2015). Endothelial-binding, proinflammatory T cells identified by MCAM (CD146) expression: characterization and role in human autoimmune diseases. Autoimmun Rev 14, 415–422.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dagur, P.K., Tatlici, G., Gourley, M., Samsel, L., Raghavachari, N., Liu, P., Liu, D., and McCoy Jr., J.P. (2010). CD146+ T lymphocytes are increased in both the peripheral circulation and in the synovial effusions of patients with various musculoskeletal diseases and display pro-inflammatory gene profiles. Cytometry Part B Clin 78B, 88–95.

    Article  CAS  Google Scholar 

  • de la Higuera, L., López-García, M., Castro, M., Abourashchi, N., Lythe, G., and Molina-París, C. (2019). Fate of a naive T cell: a stochastic journey. Front Immunol 10, 194.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de la Roche, M., Asano, Y., and Griffiths, G.M. (2016). Origins of the cytolytic synapse. Nat Rev Immunol 16, 421–432.

    Article  CAS  PubMed  Google Scholar 

  • Dejana, E., Hirschi, K.K., and Simons, M. (2017). The molecular basis of endothelial cell plasticity. Nat Commun 8, 14361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dinsmore, C.J., and Soriano, P. (2018). MAPK and PI3K signaling: at the crossroads of neural crest development. Dev Biol 444, S79–S97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dobson, R., and Giovannoni, G. (2019). Multiple sclerosis—a review. Euro J Neurol 26, 27–40.

    Article  CAS  Google Scholar 

  • Dominici, M., Le Blanc, K., Mueller, I., Slaper-Cortenbach, I., Marini, F.C., Krause, D. S., Deans, R.J., Keating, A., Prockop, D.J., and Horwitz, E.M. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement. Cytotherapy 8, 315–317.

    Article  CAS  PubMed  Google Scholar 

  • Dong, J., Zhao, Y., Huang, Q., Fei, X., Diao, Y., Shen, Y., Xiao, H., Zhang, T., Lan, Q., and Gu, X. (2011). Glioma stem/progenitor cells contribute to neovascularization via transdifferentiation. Stem Cell Rev Rep 7, 141–152.

    Article  PubMed  Google Scholar 

  • Dongre, A., and Weinberg, R.A. (2019). New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol 20, 69–84.

    Article  CAS  PubMed  Google Scholar 

  • Duan, H., Jing, L., Jiang, X., Ma, Y., Wang, D., Xiang, J., Chen, X., Wu, Z., Yan, H., Jia, J., et al. (2021a). CD146 bound to LCK promotes T cell receptor signaling and antitumor immune responses in mice. J Clin Invest 131, e148568.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duan, H., Jing, L., Xiang, J., Ju, C., Wu, Z., Liu, J., Ma, X., Chen, X., Liu, Z., Feng, J., et al. (2022). CD146 associates with Gp130 to control a macrophage pro-inflammatory program that regulates the metabolic response to obesity. Adv Sci 9, e2103719.

    Article  Google Scholar 

  • Duan, H., Xing, S., Luo, Y., Feng, L., Gramaglia, I., Zhang, Y., Lu, D., Zeng, Q., Fan, K., Feng, J., et al. (2013). Targeting endothelial CD146 attenuates neuroinflammation by limiting lymphocyte extravasation to the CNS. Sci Rep 3, 1687.

    Article  PubMed  PubMed Central  Google Scholar 

  • Duan, H.X., Xiong, C.L., Jing, L., Xu, Q.J., Liu, J.Y., Ma, X.R., Wang, D.J., Xiang, J.Q., He, Z.H., Feng, J., et al. (2020). Review and prospect of CD146 research (in Chinese). Sci Sin Vitae 50, 1339–1387.

    Article  Google Scholar 

  • Duan, H., Zhao, S., Xiang, J., Ju, C., Chen, X., Gramaglia, I., and Yan, X. (2021b). Targeting the CD146/Galectin-9 axis protects the integrity of the blood-brain barrier in experimental cerebral malaria. Cell Mol Immunol 18, 2443–2454.

    Article  CAS  PubMed  Google Scholar 

  • Dudzik, P., Trojan, S.E., Ostrowska, B., Zemanek, G., Dulińska-litewka, J., Laidler, P., and Kocemba-pilarczyk, K.A. (2019). The epigenetic modifier 5-Aza-2-deoxycytidine triggers the expression of CD146 gene in prostate cancer cells. Anticancer Res 39, 2395–2403.

    Article  CAS  PubMed  Google Scholar 

  • Dufies, M., Nollet, M., Ambrosetti, D., Traboulsi, W., Viotti, J., Borchiellini, D., Grépin, R., Parola, J., Giuliano, S., Helley-Russick, D., et al. (2018). Soluble CD146 is a predictive marker of pejorative evolution and of sunitinib efficacy in clear cell renal cell carcinoma. Theranostics 8, 2447–2458.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • DuPage, M., and Bluestone, J.A. (2016). Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease. Nat Rev Immunol 16, 149–163.

    Article  CAS  PubMed  Google Scholar 

  • Elshal, M.F., Khan, S.S., Takahashi, Y., Solomon, M.A., and McCoy Jr, J.P. (2005). CD146 (Mel-CAM), an adhesion marker of endothelial cells, is a novel marker of lymphocyte subset activation in normal peripheral blood. Blood 106, 2923–2924.

    Article  CAS  PubMed  Google Scholar 

  • Ervin, E.H., French, R., Chang, C.H., and Pauklin, S. (2022). Inside the stemness engine: mechanistic links between deregulated transcription factors and stemness in cancer. Semin Cancer Biol 87, 48–83.

    Article  CAS  PubMed  Google Scholar 

  • Espin-Palazon, R., and Traver, D. (2016). The NF-κB family: key players during embryonic development and HSC emergence. Exp Hematol 44, 519–527.

    Article  CAS  PubMed  Google Scholar 

  • Falzone, L., Candido, S., Docea, A.O., and Calina, D. (2022). Editorial: Inflammation and aging in chronic and degenerative diseases: Current and future therapeutic strategies. Front Pharmacol 13, 1122786.

    Article  PubMed  Google Scholar 

  • Fang, X., Cai, Y., Xu, Y., and Zhang, H. (2022). Exosome-mediated lncRNA SNHG11 regulates angiogenesis in pancreatic carcinoma through miR-324-3p/VEGFA axis. Cell Biol Int 46, 106–117.

    Article  CAS  PubMed  Google Scholar 

  • Fehm, T.N., Blassl, C., Kuhlmann, J.D., Webers, A., Wimberger, P., and Neubauer, H. (2016). Gene expression profiling of single circulating tumor cells in ovarian cancer: establishment of a multi-marker gene panel. Mol Oncol 10, 1030–1042.

    Article  PubMed  PubMed Central  Google Scholar 

  • Flanagan, K., Fitzgerald, K., Baker, J., Regnstrom, K., Gardai, S., Bard, F., Mocci, S., Seto, P., You, M., Larochelle, C., et al. (2012). Laminin-411 is a vascular ligand for MCAM and facilitates TH17 cell entry into the CNS. PLoS ONE 7, e40443.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Forcade, E., Paz, K., Flynn, R., Griesenauer, B., Amet, T., Li, W., Liu, L., Bakoyannis, G., Jiang, D., Chu, H.W., et al. (2017). An activated Th17-prone T cell subset involved in chronic graft-versus-host disease sensitive to pharmacological inhibition. JCI Insight 2, e92111.

    Article  PubMed  PubMed Central  Google Scholar 

  • Friedenstein, A.J., Petrakova, K.V., Kurolesova, A.I., and Frolova, G.P. (1968). Heterotopic transplants of bone marrow. Transplant 6, 230–247.

    Article  CAS  Google Scholar 

  • Friedenstein, A.J., Piatetzky-Shapiro, and Petrakova, K.V. (1966). Osteogenesis in transplants of bone marrow cells. Dev 16, 381–390.

    Article  CAS  Google Scholar 

  • Gao, Q., Zhang, J., Wang, X., Liu, Y., He, R., Liu, X., Wang, F., Feng, J., Yang, D., Wang, Z., et al. (2017). The signalling receptor MCAM coordinates apical-basal polarity and planar cell polarity during morphogenesis. Nat Commun 8, 15279.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garibaldi, S., Barisione, C., Ghigliotti, G., Spallarossa, P., Barsotti, A., Fabbi, P., Corsiglia, L., Palmieri, D., Palombo, D., and Brunelli, C. (2012). Soluble form of the endothelial adhesion molecule CD146 binds preferentially CD16+ monocytes. Mol Biol Rep 39, 6745–6752.

    Article  CAS  PubMed  Google Scholar 

  • Geginat, J., Paroni, M., Maglie, S., Alfen, J.S., Kastirr, I., Gruarin, P., De Simone, M., Pagani, M., and Abrignani, S. (2014). Plasticity of human CD4 T Cell Subsets. Front Immunol 5, 630.

    Article  PubMed  PubMed Central  Google Scholar 

  • Grneberg, H. (1958). The strategy of the genes. Ann Hum Genet 15.

  • Hegazy, A.N., Peine, M., Helmstetter, C., Panse, I., Fröhlich, A., Bergthaler, A., Flatz, L., Pinschewer, D.D., Radbruch, A., and Löhning, M. (2010). Interferons direct Th2 cell reprogramming to generate a stable GATA-3+T-bet+ cell subset with combined Th2 and Th1 cell functions. Immun 32, 116–128.

    Article  CAS  Google Scholar 

  • Heim, X., Bermudez, J., Joshkon, A., Kaspi, E., Bachelier, R., Nollet, M., Vélier, M., Dou, L., Brodovitch, A., Foucault-Bertaud, A., et al. (2022). CD146 at the interface between oxidative stress and the Wnt signaling pathway in systemic sclerosis. J Investig Dermatol 142, 3200–3210.e5.

    Article  CAS  PubMed  Google Scholar 

  • Hirota, K., Duarte, J.H., Veldhoen, M., Hornsby, E., Li, Y., Cua, D.J., Ahlfors, H., Wilhelm, C., Tolaini, M., Menzel, U., et al. (2011). Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol 12, 255–263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huelsken, J., Vogel, R., Brinkmann, V., Erdmann, B., Birchmeier, C., and Birchmeier, W. (2000). Requirement for β-catenin in anterior-posterior axis formation in mice. J Cell Biol 148, 567–578.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Imbert, A.M., Garulli, C., Choquet, E., Koubi, M., Aurrand-Lions, M., and Chabannon, C. (2012). CD146 expression in human breast cancer cell lines induces phenotypic and functional changes observed in epithelial to mesenchymal transition. PLoS ONE 7, e43752.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ishii, G., Ochiai, A., and Neri, S. (2016). Phenotypic and functional heterogeneity of cancer-associated fibroblast within the tumor microenvironment. Adv Drug Deliver Rev 99, 186–196.

    Article  CAS  Google Scholar 

  • Jessen, K.R., and Mirsky, R. (2016). The repair Schwann cell and its function in regenerating nerves. J Physiol 594, 3521–3531.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang, G., Zhang, L., Zhu, Q., Bai, D., Zhang, C., and Wang, X. (2016). CD146 promotes metastasis and predicts poor prognosis of hepatocellular carcinoma. J Exp Clin Cancer Res 35, 38.

    Article  PubMed  PubMed Central  Google Scholar 

  • Jiang, R.C., Zheng, X.Y., Yang, S.L., Shi, H.J., Xi, J.H., Zou, Y.J., Dou, H.Q., Wang, Y.J., Qin, Y., Zhang, X.L., et al. (2022). CD146 mediates the anti-apoptotic role of Netrin-1 in endothelial progenitor cells under hypoxic conditions. Mol Med Rep 25, 5.

    Article  CAS  PubMed  Google Scholar 

  • Jiang, T., Zhuang, J., Duan, H., Luo, Y., Zeng, Q., Fan, K., Yan, H., Lu, D., Ye, Z., Hao, J., et al. (2012). CD146 is a coreceptor for VEGFR-2 in tumor angiogenesis. Blood 120, 2330–2339.

    Article  CAS  PubMed  Google Scholar 

  • Jin, H.J., Kwon, J.H., Kim, M., Bae, Y.K., Choi, S.J., Oh, W., Yang, Y.S., and Jeon, H.B. (2016). Downregulation of melanoma cell adhesion molecule (MCAM/CD146) accelerates cellular senescence in human umbilical cord blood-derived mesenchymal stem cells. Stem Cells Transl Med 5, 427–439.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jing, L., An, Y., Cai, T., Xiang, J., Li, B., Guo, J., Ma, X., Wei, L., Tian, Y., Cheng, X., et al. (2023). A subpopulation of CD146+ macrophages enhances antitumor immunity by activating the NLRP3 inflammasome. Cell Mol Immunol 20, 908–923.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Joshkon, A., Tabouret, E., Traboulsi, W., Bachelier, R., Simoncini, S., Roffino, S., Jiguet-Jiglaire, C., Badran, B., Guillet, B., Foucault-Bertaud, A., et al. (2022). Soluble CD146, a biomarker and a target for preventing resistance to anti-angiogenic therapy in glioblastoma. acta neuropathol commun 10, 151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jouve, N., Despoix, N., Espeli, M., Gauthier, L., Cypowyj, S., Fallague, K., Schiff, C., Dignat-George, F., Vély, F., and Leroyer, A.S. (2013). The involvement of CD146 and its novel ligand Galectin-1 in apoptotic regulation of endothelial cells. J Biol Chem 288, 2571–2579.

    Article  CAS  PubMed  Google Scholar 

  • Kalluri, R., and Weinberg, R.A. (2009). The basics of epithelial-mesenchymal transition. J Clin Invest 119, 1420–1428.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kamiyama, T., Watanabe, H., Iijima, M., Miyazaki, A., and Iwamoto, S. (2012). Coexpression of CCR6 and CD146 (MCAM) is a marker of effector memory T-helper 17 cells. J Dermatol 39, 838–842.

    Article  CAS  PubMed  Google Scholar 

  • Kaur, G., and Singh, N.K. (2021). The role of inflammation in retinal neurodegeneration and degenerative diseases. Int J Mol Sci 23, 386.

    Article  PubMed  PubMed Central  Google Scholar 

  • Kim, C.H., Taira, E., Kuo, C.H., Li, B.S., Okamoto, H., Nakahira, K., Ikenaka, K., Higuchi, H., and Miki, N. (1996). Neuron-specific expression of a chicken gicerin cDNA in transient transgenic zebrafish. Neurochem Res 21, 231–237.

    Article  CAS  PubMed  Google Scholar 

  • Kim, K., Huang, H., Parida, P.K., He, L., Marquez-Palencia, M., Reese, T.C., Kapur, P., Brugarolas, J., Brekken, R.A., and Malladi, S. (2023). Cell competition shapes metastatic latency and relapse. Cancer Discov 13, 85–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim, K.R., Jun, S.Y., Kim, J.Y., and Ro, J.Y. (2004). Implantation site intermediate trophoblasts in placenta cretas. Modern Pathol 17, 1483–1490.

    Article  Google Scholar 

  • Kobayashi, H., Enomoto, A., Woods, S.L., Burt, A.D., Takahashi, M., and Worthley, D. L. (2019). Cancer-associated fibroblasts in gastrointestinal cancer. Nat Rev Gastroenterol Hepatol 16, 282–295.

    Article  PubMed  Google Scholar 

  • Kobayashi, H., Gieniec, K.A., Lannagan, T.R.M., Wang, T., Asai, N., Mizutani, Y., Iida, T., Ando, R., Thomas, E.M., Sakai, A., et al. (2022). The origin and contribution of cancer-associated fibroblasts in colorectal carcinogenesis. Gastroenterol 162, 890–906.

    Article  CAS  Google Scholar 

  • Komichi, S., Takahashi, Y., Okamoto, M., Ali, M., Watanabe, M., Huang, H., Nakai, T., Cooper, P., and Hayashi, M. (2019). Protein S100-A7 derived from digested dentin is a critical molecule for dentin pulp regeneration. Cells 8, 1002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Larochelle, C., Cayrol, R., Kebir, H., Alvarez, J.I., Lécuyer, M.A., Ifergan, I., Viel, É., Bourbonnière, L., Beauseigle, D., Terouz, S., et al. (2012). Melanoma cell adhesion molecule identifies encephalitogenic T lymphocytes and promotes their recruitment to the central nervous system. Brain 135, 2906–2924.

    Article  PubMed  Google Scholar 

  • Lehmann, J.M., Holzmann, B., Breitbart, E.W., Schmiegelow, P., Riethmüller, G., and Johnson, J.P. (1987). Discrimination between benign and malignant cells of melanocytic lineage by two novel antigens, a glycoprotein with a molecular weight of 113,000 and a protein with a molecular weight of 76,0001. Cancer Res 47, 841–845.

    CAS  PubMed  Google Scholar 

  • Lehmann, J.M., Riethmuller, G., and Johnson, J.P. (1989). MUC18, a marker of tumor progression in human melanoma, shows sequence similarity to the neural cell adhesion molecules of the immunoglobulin superfamily. Proc Natl Acad Sci USA 86, 9891–9895.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li, W., Liu, L., Gomez, A., Zhang, J., Ramadan, A., Zhang, Q., Choi, S.W., Zhang, P., Greenson, J.K., Liu, C., et al. (2016). Proteomics analysis reveals a Th17-prone cell population in presymptomatic graft-versus-host disease. JCI Insight 1.

  • Li, X., Wang, Y., Zhang, Y., and Liu, B. (2022). Overexpression of MCAM induced by SMYD2-H3K36me2 in breast cancer stem cell properties. Breast Cancer 29, 854–868.

    Article  PubMed  Google Scholar 

  • Li, Y.Q., Gong, Y., Hou, S., Huang, T., Wang, H., Liu, D., Ni, Y., Wang, C., Wang, J., Hou, J., et al. (2021). Spatiotemporal and functional heterogeneity of hematopoietic stem cell-competent hemogenic endothelial cells in mouse embryos. Front Cell Dev Biol 9, 699263.

    Article  PubMed  PubMed Central  Google Scholar 

  • Liang, Y., Voshart, D., Paridaen, J.T.M.L., Oosterhof, N., Liang, D., Thiruvalluvan, A., Zuhorn, I.S., den Dunnen, W.F.A., Zhang, G., Lin, H., et al. (2022). CD146 increases stemness and aggressiveness in glioblastoma and activates YAP signaling. Cell Mol Life Sci 79, 398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liang, Y.K., Zeng, D., Xiao, Y.S., Wu, Y., Ouyang, Y.X., Chen, M., Li, Y.C., Lin, H.Y., Wei, X.L., Zhang, Y.Q., et al. (2017). MCAM/CD146 promotes tamoxifen resistance in breast cancer cells through induction of epithelial-mesenchymal transition, decreased ERα expression and AKT activation. Cancer Lett 386, 65–76.

    Article  CAS  PubMed  Google Scholar 

  • Libby, P. (2021). The changing landscape of atherosclerosis. Nature 592, 524–533.

    Article  CAS  PubMed  Google Scholar 

  • Liston, A., and Gray, D.H.D. (2014). Homeostatic control of regulatory T cell diversity. Nat Rev Immunol 14, 154–165.

    Article  CAS  PubMed  Google Scholar 

  • Liu, J., Smith, S., and Wang, C. (2022). Reversing the epithelial-mesenchymal transition in metastatic cancer cells using CD146-targeted black phosphorus nanosheets and a mild photothermal treatment. ACS Nano 16, 3208–3220.

    Article  CAS  PubMed  Google Scholar 

  • Liu, J., Zhang, X., Cheng, Y., and Cao, X. (2021). Dendritic cell migration in inflammation and immunity. Cell Mol Immunol 18, 2461–2471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu, Q., Yan, X., Li, Y., Zhang, Y., Zhao, X., and Shen, Y. (2004a). Pre-eclampsia is associated with the failure of melanoma cell adhesion molecule (MCAM/CD146) expression by intermediate trophoblast. Lab Invest 84, 221–228.

    Article  CAS  PubMed  Google Scholar 

  • Liu, Q., Zhao, X.G., Zhang, Y., Shen, Y., Liu, Y.X., and Yan, X.Y. (2004b). Melanoma cell adhesion molecule (MCAM/CD146) is a critical molecule in trophoblast invasion. Prog Biochem Biophys 31, 309–312.

    CAS  Google Scholar 

  • Liu, S., Cong, Y., Wang, D., Sun, Y., Deng, L., Liu, Y., Martin-Trevino, R., Shang, L., McDermott, S.P., Landis, M.D., et al. (2014). Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Rep 2, 78–91.

    Article  CAS  Google Scholar 

  • Liu, W.F., Ji, S.R., Sun, J.J., Zhang, Y., Liu, Z.Y., Liang, A.B., and Zeng, H.Z. (2012). CD146 expression correlates with epithelial-mesenchymal transition markers and a poor prognosis in gastric cancer. Int J Mol Sci 13, 6399–6406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lugassy, C., Kleinman, H.K., Vermeulen, P.B., and Barnhill, R.L. (2020). Angiotropism, pericytic mimicry and extravascular migratory metastasis: an embryogenesis-derived program of tumor spread. Angiogenesis 23, 27–41.

    Article  CAS  PubMed  Google Scholar 

  • Lugassy, C., Péault, B., Wadehra, M., Kleinman, H.K., and Barnhill, R.L. (2013a). Could pericytic mimicry represent another type of melanoma cell plasticity with embryonic properties? Pigment Cell Melanoma Res 26, 746–754.

    Article  PubMed  Google Scholar 

  • Lugassy, C., Wadehra, M., Li, X., Corselli, M., Akhavan, D., Binder, S.W., Péault, B., Cochran, A.J., Mischel, P.S., Kleinman, H.K., et al. (2013b). Pilot study on “pericytic mimicry” and potential embryonic/stem cell properties of angiotropic melanoma cells interacting with the abluminal vascular surface. Cancer Microenviron 6, 19–29.

    Article  CAS  PubMed  Google Scholar 

  • Luo, Y., Duan, H., Qian, Y., Feng, L., Wu, Z., Wang, F., Feng, J., Yang, D., Qin, Z., and Yan, X. (2017). Macrophagic CD146 promotes foam cell formation and retention during atherosclerosis. Cell Res 27, 352–372.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luo, Y., Teng, X., Zhang, L., Chen, J., Liu, Z., Chen, X., Zhao, S., Yang, S., Feng, J., and Yan, X. (2019). CD146-HIF-1α hypoxic reprogramming drives vascular remodeling and pulmonary arterial hypertension. Nat Commun 10, 3551.

    Article  PubMed  PubMed Central  Google Scholar 

  • Luond, F., Sugiyama, N., Bill, R., Bornes, L., Hager, C., Tang, F., Santacroce, N., Beisel, C., Ivanek, R., Bürglin, T., et al. (2021). Distinct contributions of partial and full EMT to breast cancer malignancy. Dev Cell 56, 3203–3221.e11.

    Article  CAS  PubMed  Google Scholar 

  • Ma, L., Huang, Z., Wu, D., Kou, X., Mao, X., and Shi, S. (2021). CD146 controls the quality of clinical grade mesenchymal stem cells from human dental pulp. Stem Cell Res Ther 12, 488.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma, X., Wang, J., Liu, J., Mo, Q., Yan, X., Ma, D., and Duan, H. (2017). Targeting CD146 in combination with vorinostat for the treatment of ovarian cancer cells. Oncol Lett 13, 1681–1687.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma, Y., Zhang, H., Xiong, C., Liu, Z., Xu, Q., Feng, J., Zhang, J., Wang, Z., and Yan, X. (2018). CD146 mediates an E-cadherin-to-N-cadherin switch during TGF-β signaling-induced epithelial-mesenchymal transition. Cancer Lett 430, 201–214.

    Article  CAS  PubMed  Google Scholar 

  • Mae, M.A., He, L., Nordling, S., Vazquez-Liebanas, E., Nahar, K., Jung, B., Li, X., Tan, B.C., Chin Foo, J., Cazenave-Gassiot, A., et al. (2021). Single-cell analysis of blood-brain barrier response to pericyte loss. Circ Res 128, e46.

    Article  PubMed  Google Scholar 

  • Matkar, P.N., Singh, K.K., Prud’homme, G., and Leong-Poi, H. (2015). Abstract 4171: novel regulatory role of Neuropilin-1 in endothelial to mesenchymal transition as a potential source of carcinoma associated fibroblasts. Cancer Res 75, 4171.

    Article  Google Scholar 

  • Matsui, M., Kobayashi, T., and Tsutsui, T.W. (2018). CD146 positive human dental pulp stem cells promote regeneration of dentin/pulp-like structures. Hum Cell 31, 127–138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meacham, C.E., and Morrison, S.J. (2013). Tumour heterogeneity and cancer cell plasticity. Nature 501, 328–337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Medic, S., and Ziman, M. (2010). PAX3 expression in normal skin melanocytes and melanocytic lesions (naevi and melanomas). PLoS ONE 5, e9977.

    Article  PubMed  PubMed Central  Google Scholar 

  • Merrell, A.J., and Stanger, B.Z. (2016). Adult cell plasticity in vivo: de-differentiation and transdifferentiation are back in style. Nat Rev Mol Cell Biol 17, 413–425.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mills, J.C., Stanger, B.Z., and Sander, M. (2019). Nomenclature for cellular plasticity: are the terms as plastic as the cells themselves? EMBO J 38, e103148.

    Article  PubMed  PubMed Central  Google Scholar 

  • Mills, L., Tellez, C., Huang, S., Baker, C., McCarty, M., Green, L., Gudas, J.M., Feng, X., and Bar-Eli, M. (2002). Fully human antibodies to MCAM/MUC18 inhibit tumor growth and metastasis of human melanoma. Cancer Res 62, 5106–5114.

    CAS  PubMed  Google Scholar 

  • Min, Q., Parkinson, D.B., and Dun, X.E. (2021). Migrating Schwann cells direct axon regeneration within the peripheral nerve bridge. Glia 69, 235–254.

    Article  PubMed  Google Scholar 

  • Mosser, D.M., and Edwards, J.P. (2008). Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8, 958–969.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nomikou, E., Alexopoulou, A., Vasilieva, L., Agiasotelli, D., Pavlou, E., Theodossiades, G., and Dourakis, S.P. (2015). Soluble CD146, a novel endothelial marker, is related to the severity of liver disease. Scand J Gastroenterol 50, 577–583.

    Article  CAS  PubMed  Google Scholar 

  • Oka, S., Uramoto, H., Chikaishi, Y., and Tanaka, F. (2012). The expression of CD146 predicts a poor overall survival in patients with adenocarcinoma of the lung. Anticancer Res 32, 861–864.

    PubMed  Google Scholar 

  • Olsen, J. J., Pohl, S. Ö., Deshmukh, A., Visweswaran, M., Ward, N. C., Arfuso, F., Agostino, M., and Dharmarajan, A. (2017). The role of Wnt signalling in angiogenesis. Clinical Biochem Rev, 38: 131–142.

    Google Scholar 

  • Otsuki, S., Saito, T., Taylor, S., Li, D., Moonen, J.R., Marciano, D.P., Harper, R.L., Cao, A., Wang, L., Ariza, M.E., et al. (2021). Monocyte released HERV-K dUTPase engages TLR4 and MCAM causing endothelial mesenchymal transition. JCI Insight 6.

  • Pachon-Pena, G., Yu, G., Tucker, A., Wu, X., Vendrell, J., Bunnell, B.A., and Gimble, J. M. (2011). Stromal stem cells from adipose tissue and bone marrow of age-matched female donors display distinct immunophenotypic profiles. J Cell Physiol 226, 843–851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pickl, W.F., Majdic, O., Fischer, G.F., Petzelbauer, P., Faé, I., Waclavicek, M., Stöckl, J., Scheinecker, C., Vidicki, T., Aschauer, H., et al. (1997). MUC18/MCAM (CD146), an activation antigen of human T lymphocytes. J Immunol 158, 2107–2115.

    Article  CAS  PubMed  Google Scholar 

  • Pilz, G.A., Ulrich, C., Ruh, M., Abele, H., Schäfer, R., Kluba, T., Bühring, H.J., Rolauffs, B., and Aicher, W.K. (2011). Human term placenta-derived mesenchymal stromal cells are less prone to osteogenic differentiation than bone marrow-derived mesenchymal stromal cells. Stem Cells Dev 20, 635–646.

    Article  CAS  PubMed  Google Scholar 

  • Qian, Y.N., Luo, Y.T., Duan, H.X., Feng, L.Q., Bi, Q., Wang, Y.J., and Yan, X.Y. (2014). Adhesion molecule CD146 and its soluble form correlate well with carotid atherosclerosis and plaque instability. CNS Neurosci Ther 20, 438–445.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rao, C., Su, Z., Li, H., Ma, X., Zheng, X., Liu, Y., Lu, F., Qu, J., and Hou, L. (2016). Microphthalmia-associated transcription factor regulates skin melanoblast migration by repressing the melanoma cell adhesion molecule. Exp Dermatol 25, 74–76.

    Article  PubMed  Google Scholar 

  • Ricci-Vitiani, L., Pallini, R., Biffoni, M., Todaro, M., Invernici, G., Cenci, T., Maira, G., Parati, E.A., Stassi, G., Larocca, L.M., et al. (2010). Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 468, 824–828.

    Article  CAS  PubMed  Google Scholar 

  • Rodewald, A.K., Rushing, E.J., Kirschenbaum, D., Mangana, J., Mittmann, C., Moch, H., Lugassy, C., Barnhill, R.L., and Mihic-Probst, D. (2019). Eight autopsy cases of melanoma brain metastases showing angiotropism and pericytic mimicry. Implications for extravascular migratory metastasis. J Cutan Pathol 46, 570–578.

    Article  PubMed  Google Scholar 

  • Roesch, A., Fukunaga-Kalabis, M., Schmidt, E.C., Zabierowski, S.E., Brafford, P.A., Vultur, A., Basu, D., Gimotty, P., Vogt, T., and Herlyn, M. (2010). A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell 141, 583–594.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roostalu, U., Aldeiri, B., Albertini, A., Humphreys, N., Simonsen-Jackson, M., Wong, J.K.F., and Cossu, G. (2018). Distinct cellular mechanisms underlie smooth muscle turnover in vascular development and repair. Circ Res 122, 267–281.

    Article  CAS  PubMed  Google Scholar 

  • Russell, K.C., Phinney, D.G., Lacey, M.R., Barrilleaux, B.L., Meyertholen, K.E., and O’Connor, K.C. (2010). 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, 788–798.

    Article  CAS  PubMed  Google Scholar 

  • Sadeghi, R.S., Kulej, K., Kathayat, R.S., Garcia, B.A., Dickinson, B.C., Brady, D.C., and Witze, E.S. (2018). Wnt5a signaling induced phosphorylation increases APT1 activity and promotes melanoma metastatic behavior. eLife 7, e34362.

    Article  PubMed  PubMed Central  Google Scholar 

  • Sahai, E., Astsaturov, I., Cukierman, E., DeNardo, D.G., Egeblad, M., Evans, R.M., Fearon, D., Greten, F.R., Hingorani, S.R., Hunter, T., et al. (2020). A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer 20, 174–186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schneider-Hohendorf, T., Rossaint, J., Mohan, H., Böning, D., Breuer, J., Kuhlmann, T., Gross, C.C., Flanagan, K., Sorokin, L., Vestweber, D., et al. (2014). VLA-4 blockade promotes differential routes into human CNS involving PSGL-1 rolling of T cells and MCAM-adhesion of TH17 cells. J Exp Med 211, 1833–1846.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schwab, K.E., Hutchinson, P., and Gargett, C.E. (2008). Identification of surface markers for prospective isolation of human endometrial stromal colony-forming cells. Hum Reprod 23, 934–943.

    Article  CAS  PubMed  Google Scholar 

  • Seftalioglu, A., and Karakoc, L. (2000). Expression of CD146 adhesion molecules (MUC18 or MCAM) in the thymic microenvironment. Acta Histochemica 102, 69–83.

    Article  CAS  PubMed  Google Scholar 

  • Sharma, A., Joshkon, A., Ladjimi, A., Traboulsi, W., Bachelier, R., Robert, S., Foucault-Bertaud, A., Leroyer, A.S., Bardin, N., Somasundaram, I., et al. (2022). Soluble CD146 as a potential target for preventing triple negative breast cancer MDA-MB-231 cell growth and dissemination. Int J Mol Sci 23, 974.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shen, J., Shrestha, S., Rao, P.N., Asatrian, G., Scott, M.A., Nguyen, V., Giacomelli, P., Soo, C., Ting, K., Eilber, F.C., et al. (2016). Pericytic mimicry in well-differentiated liposarcoma/atypical lipomatous tumor. Hum Pathol 54, 92–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shen, S., and Clairambault, J. (2020). Cell plasticity in cancer cell populations. F1000Res 9, 635.

    Article  CAS  Google Scholar 

  • Shen, Y., Zhu, J., Liu, Q., Ding, S., Dun, X., and He, J. (2021). Up-regulation of CD146 in Schwann cells following peripheral nerve injury modulates schwann cell function in regeneration. Front Cell Neurosci 15, 743532.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siemerink, M.J., Klaassen, I., Van Noorden, C.J.F., and Schlingemann, R.O. (2013). Endothelial tip cells in ocular angiogenesis. J Histochem Cytochem 61, 101–115.

    Article  PubMed  PubMed Central  Google Scholar 

  • So, J.H., Hong, S.K., Kim, H.T., Jung, S.H., Lee, M.S., Choi, J.H., Bae, Y.K., Kudoh, T., Kim, J.H., and Kim, C.H. (2010). Gicerin/CD146 is involved in zebrafish cardiovascular development and tumor angiogenesis. Genes Cells 15, 1099–1110.

    Article  CAS  PubMed  Google Scholar 

  • Soda, Y., Marumoto, T., Friedmann-Morvinski, D., Soda, M., Liu, F., Michiue, H., Pastorino, S., Yang, M., Hoffman, R.M., Kesari, S., et al. (2011). Transdifferentiation of glioblastoma cells into vascular endothelial cells. Proc Natl Acad Sci USA 108, 4274–4280.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Staal, F.J., and Sen, J.M. (2008). The canonical Wnt signaling pathway plays an important role in lymphopoiesis and hematopoiesis. Eur J Immunol 38, 1788–1794.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Stalin, J., Nollet, M., Garigue, P., Fernandez, S., Vivancos, L., Essaadi, A., Muller, A., Bachelier, R., Foucault-Bertaud, A., Fugazza, L., et al. (2016). Targeting soluble CD146 with a neutralizing antibody inhibits vascularization, growth and survival of CD146-positive tumors. Oncogene 35, 5489–5500.

    Article  CAS  PubMed  Google Scholar 

  • Stalin, J., Traboulsi, W., Vivancos-Stalin, L., Nollet, M., Joshkon, A., Bachelier, R., Guillet, B., Lacroix, R., Foucault-Bertaud, A., Leroyer, A.S., et al. (2020). Therapeutic targeting of soluble CD146/MCAM with the M2J-1 monoclonal antibody prevents metastasis development and procoagulant activity in CD146-positive invasive tumors. Intl J Cancer 147, 1666–1679.

    Article  CAS  Google Scholar 

  • Steinhart, Z., and Angers, S. (2018). Wnt signaling in development and tissue homeostasis. Dev 145, dev146589.

    Article  Google Scholar 

  • Sward, K., Krawczyk, K.K., Morén, B., Zhu, B., Matic, L., Holmberg, J., Hedin, U., Uvelius, B., Stenkula, K., and Rippe, C. (2019). Identification of the intermediate filament protein synemin/SYNM as a target of myocardin family coactivators. Am J Physiol Cell Physiol 317, C1128–C1142.

    Article  PubMed  Google Scholar 

  • Taira, E., Kohama, K., Tsukamoto, Y., Okumura, S., and Miki, N. (2004a). Characterization of Gicerin/MUC18/CD146 in the rat nervous system. J Cell Physiol 198, 377–387.

    Article  CAS  PubMed  Google Scholar 

  • Taira, E., Kohama, K., Tsukamoto, Y., Okumura, S., and Miki, N. (2005). Gicerin/CD146 is involved in neurite extension of NGF-treated PC12 cells. J Cell Physiol 204, 632–637.

    Article  CAS  PubMed  Google Scholar 

  • Taira, E., Nagino, T., Taniura, H., Takaha, N., Kim, C.H., Kuo, C.H., Li, B.S., Higuchi, H., and Miki, N. (1995). Expression and functional analysis of a novel isoform of gicerin, an immunoglobulin superfamily cell adhesion molecule. J Biol Chem 270, 28681–28687.

    Article  CAS  PubMed  Google Scholar 

  • Taira, E., Nagino, T., Tsukamoto, Y., Ding, Y., Sakuma, S., and Miki, N. (1998). Neurite promotion from ciliary ganglion neurons by gicerin. Neurochem Int 32, 23–29.

    Article  CAS  PubMed  Google Scholar 

  • Taira, E., Tsukamoto, Y., Kohama, K., Maeda, M., Kiyama, H., and Miki, N. (2004b). Expression and involvement of gicerin, a cell adhesion molecule, in the development of chick optic tectum. J Neurochem 88, 891–899.

    Article  CAS  PubMed  Google Scholar 

  • Taniura, H., Kuo, C.H., Hayashi, Y., and Miki, N. (1991). Purification and characterization of an 82-kD membrane protein as a neurite outgrowth factor binding protein: possible involvement of NOF binding protein in axonal outgrowth in developing retina. J Cell Biol 112, 313–322.

    Article  CAS  PubMed  Google Scholar 

  • Tavangar, M.S., Hosseini, S.M., Dehghani-Nazhvani, A., and Monabati, A. (2017). Role of CD146 enrichment in purification of stem cells derived from dental pulp polyp. Iran Endod J 12, 92–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Thankamony, A.P., Saxena, K., Murali, R., Jolly, M.K., and Nair, R. (2020). Cancer stem cell plasticity—a deadly deal. Front Mol Biosci 7, 79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tripathi, S.C., Fahrmann, J.F., Celiktas, M., Aguilar, M., Marini, K.D., Jolly, M.K., Katayama, H., Wang, H., Murage, E.N., Dennison, J.B., et al. (2017). MCAM mediates chemoresistance in small-cell lung cancer via the PI3K/AKT/SOX2 signaling pathway. Cancer Res 77, 4414–4425.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsukamoto, Y., Taira, E., Nakane, Y., Tsudzuki, M., Kohama, K., Amin, H., Miki, N., and Sasaki, F. (1999). Expression of gicerin, a cell adhesion molecule, in the abnormal retina in silver plumage color mutation of Japanese quail (Coturnix japonica). Neurosci Lett 266, 53–56.

    Article  CAS  PubMed  Google Scholar 

  • Tu, T., Gao, Q., Luo, Y., Chen, J., Lu, D., Feng, J., Yang, D., Song, L., and Yan, X. (2013). CD146 deletion in the nervous system impairs appetite, locomotor activity and spatial learning in mice. PLoS ONE 8, e74124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tu, T., Zhang, C., Yan, H., Luo, Y., Kong, R., Wen, P., Ye, Z., Chen, J., Feng, J., Liu, F., et al. (2015). CD146 acts as a novel receptor for netrin-1 in promoting angiogenesis and vascular development. Cell Res 25, 275–287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tung, H.H., and Lee, S.L. (2017). Physical binding of endothelial MCAM and neural transmembrane protease matriptase—novel cell adhesion in neural stem cell vascular niche. Sci Rep 7, 4946.

    Article  PubMed  PubMed Central  Google Scholar 

  • von Ahrens, D., Bhagat, T.D., Nagrath, D., Maitra, A., and Verma, A. (2017). The role of stromal cancer-associated fibroblasts in pancreatic cancer. J Hematol Oncol 10, 76.

    Article  PubMed  PubMed Central  Google Scholar 

  • Walchli, T., Wacker, A., Frei, K., Regli, L., Schwab, M.E., Hoerstrup, S.P., Gerhardt, H., and Engelhardt, B. (2015). Wiring the vascular network with neural cues: a CNS perspective. Neuron 87, 271–296.

    Article  CAS  PubMed  Google Scholar 

  • Wang, D., Duan, H., Feng, J., Xiang, J., Feng, L., Liu, D., Chen, X., Jing, L., Liu, Z., Zhang, D., et al. (2020a). Soluble CD146, a cerebrospinal fluid marker for neuroinflammation, promotes blood-brain barrier dysfunction. Theranostics 10, 231–246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang, J., Tang, X., Weng, W., Qiao, Y., Lin, J., Liu, W., Liu, R., Ma, L., Yu, W., Yu, Y., et al. (2015a). The membrane protein melanoma cell adhesion molecule (MCAM) is a novel tumor marker that stimulates tumorigenesis in hepatocellular carcinoma. Oncogene 34, 5781–5795.

    Article  CAS  PubMed  Google Scholar 

  • Wang, R., Chadalavada, K., Wilshire, J., Kowalik, U., Hovinga, K.E., Geber, A., Fligelman, B., Leversha, M., Brennan, C., and Tabar, V. (2010). Glioblastoma stemlike cells give rise to tumour endothelium. Nature 468, 829–833.

    Article  CAS  PubMed  Google Scholar 

  • Wang, W., Runkle, K.B., Terkowski, S.M., Ekaireb, R.I., and Witze, E.S. (2015b). Protein depalmitoylation is induced by Wnt5a and promotes polarized cell behavior. J Biol Chem 290, 15707–15716.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang, Z., Xu, Q., Zhang, N., Du, X., Xu, G., and Yan, X. (2020b). CD146, from a melanoma cell adhesion molecule to a signaling receptor. Sig Transduct Target Ther 5, 148.

    Article  CAS  Google Scholar 

  • Wei, Q., Tang, Y.J., Voisin, V., Sato, S., Hirata, M., Whetstone, H., Han, I., Ailles, L., Bader, G.D., Wunder, J., et al. (2015). Identification of CD146 as a marker enriched for tumor-propagating capacity reveals targetable pathways in primary human sarcoma. Oncotarget 6, 40283–40294.

    Article  PubMed  PubMed Central  Google Scholar 

  • Willert, K., Brown, J.D., Danenberg, E., Duncan, A.W., Weissman, I.L., Reya, T., Yates Iii, J.R., and Nusse, R. (2003). Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature 423, 448–452.

    Article  CAS  PubMed  Google Scholar 

  • Witze, E.S., Connacher, M.K., Houel, S., Schwartz, M.P., Morphew, M.K., Reid, L., Sacks, D.B., Anseth, K.S., and Ahn, N.G. (2013). Wnt5a directs polarized calcium gradients by recruiting cortical endoplasmic reticulum to the cell trailing edge. Dev Cell 26, 645–657.

    Article  CAS  PubMed  Google Scholar 

  • Witze, E.S., Litman, E.S., Argast, G.M., Moon, R.T., and Ahn, N.G. (2008). Wnt5a control of cell polarity and directional movement by polarized redistribution of adhesion receptors. Science 320, 365–369.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu, C., Goodall, J.C., Busch, R., and Gaston, J.S.H. (2015). Relationship of CD146 expression to secretion of interleukin (IL)-17, IL-22 and interferon-γ by CD4+ T cells in patients with inflammatory arthritis. Clin Exp Immunol 179, 378–391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu, Q., Case, S.R., Minor, M.N., Jiang, D., Martin, R.J., Bowler, R.P., Wang, J., Hartney, J., Karimpour-Fard, A., and Chu, H.W. (2013). A novel function of MUC18. Am J Pathol 182, 819–827.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu, Z., Liu, J., Chen, G., Du, J., Cai, H., Chen, X., Ye, G., Luo, Y., Luo, Y., Zhang, L., et al. (2021). CD146 is a novel ANGPTL2 receptor that promotes obesity by manipulating lipid metabolism and energy expenditure. Adv Sci 8, 2004032.

    Article  CAS  Google Scholar 

  • Wynn, T.A., Chawla, A., and Pollard, J.W. (2013). Macrophage biology in development, homeostasis and disease. Nature 496, 445–455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wynn, T.A., and Ramalingam, T.R. (2012). Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med 18, 1028–1040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xie, H., Tranguch, S., Jia, X., Zhang, H., Das, S.K., Dey, S.K., Kuo, C.J., and Wang, H. (2008). Inactivation of nuclear Wnt-β-catenin signaling limits blastocyst competency for implantation. Dev 135, 717–727.

    Article  CAS  Google Scholar 

  • Xing, S., Luo, Y., Liu, Z., Bu, P., Duan, H., Liu, D., Wang, P., Yang, J., Song, L., Feng, J., et al. (2014). Targeting endothelial CD146 attenuates colitis and prevents colitis-associated carcinogenesis. Am J Pathol 184, 1604–1616.

    Article  CAS  PubMed  Google Scholar 

  • Xue, B., Wang, P., Yu, W., Feng, J., Li, J., Zhao, R., Yang, Z., Yan, X., and Duan, H. (2022). CD146 as a promising therapeutic target for retinal and choroidal neovascularization diseases. Sci China Life Sci 65, 1157–1170.

    Article  CAS  PubMed  Google Scholar 

  • Yan, H., Zhang, C., Wang, Z., Tu, T., Duan, H., Luo, Y., Feng, J., Liu, F., and Yan, X. (2017). CD146 is required for VEGF-C-induced lymphatic sprouting during lymphangiogenesis. Sci Rep 7, 7442.

    Article  PubMed  PubMed Central  Google Scholar 

  • Yan, X., Lin, Y., Yang, D., Shen, Y., Yuan, M., Zhang, Z., Li, P., Xia, H., Li, L., Luo, D., et al. (2003). A novel anti-CD146 monoclonal antibody, AA98, inhibits angiogenesis and tumor growth. Blood 102, 184–191.

    Article  CAS  PubMed  Google Scholar 

  • Yang, Y., Hernandez, R., Rao, J., Yin, L., Qu, Y., Wu, J., England, C.G., Graves, S.A., Lewis, C.M., Wang, P., et al. (2015). Targeting CD146 with a64 Cu-labeled antibody enables in vivo immunoPET imaging of high-grade gliomas. Proc Natl Acad Sci USA 112, E6525–E6534.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yawata, T., Higashi, Y., Kawanishi, Y., Nakajo, T., Fukui, N., Fukuda, H., and Ueba, T. (2019). CD146 is highly expressed in glioma stem cells and acts as a cell cycle regulator. J Neurooncol 144, 21–32.

    Article  CAS  PubMed  Google Scholar 

  • Ye, Z., Zhang, C., Tu, T., Sun, M., Liu, D., Lu, D., Feng, J., Yang, D., Liu, F., and Yan, X. (2013). Wnt5a uses CD146 as a receptor to regulate cell motility and convergent extension. Nat Commun 4, 2803.

    Article  PubMed  Google Scholar 

  • Yin, Z., Dong, C., Jiang, K., Xu, Z., Li, R., Guo, K., Shao, S., and Wang, L. (2019). Heterogeneity of cancer-associated fibroblasts and roles in the progression, prognosis, and therapy of hepatocellular carcinoma. J Hematol Oncol 12, 101.

    Article  PubMed  PubMed Central  Google Scholar 

  • Yuan, S., Norgard, R.J., and Stanger, B.Z. (2019). Cellular plasticity in cancer. Cancer Discov 9, 837–851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zabouo, G., Imbert, A.M., Jacquemier, J., Finetti, P., Moreau, T., Esterni, B., Birnbaum, D., Bertucci, F., and Chabannon, C. (2009). CD146 expression is associated with a poor prognosis in human breast tumors and with enhanced motility in breast cancer cell lines. Breast Cancer Res 11, R1.

    Article  PubMed  PubMed Central  Google Scholar 

  • Zeisberg, E.M., Potenta, S., Xie, L., Zeisberg, M., and Kalluri, R. (2007). Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res 67, 10123–10128.

    Article  CAS  PubMed  Google Scholar 

  • Zeng, G., Cai, S., and Wu, G.J. (2011). Up-regulation of METCAM/MUC18 promotes motility, invasion, and tumorigenesis of human breast cancer cells. BMC Cancer 11, 113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zeng, Q., Li, W., Lu, D., Wu, Z., Duan, H., Luo, Y., Feng, J., Yang, D., Fu, L., and Yan, X. (2012). CD146, an epithelial-mesenchymal transition inducer, is associated with triple-negative breast cancer. Proc Natl Acad Sci USA 109, 1127–1132.

    Article  CAS  PubMed  Google Scholar 

  • Zeng, Q., Wu, Z., Duan, H., Jiang, X., Tu, T., Lu, D., Luo, Y., Wang, P., Song, L., Feng, J., et al. (2014a). Impaired tumor angiogenesis and VEGF-induced pathway in endothelial CD146 knockout mice. Protein Cell 5, 445–456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zeng, Q., Zhang, P., Wu, Z., Xue, P., Lu, D., Ye, Z., Zhang, X., Huang, Z., Feng, J., Song, L., et al. (2014b). Quantitative proteomics reveals ER-α involvement in CD146-induced epithelial-mesenchymal transition in breast cancer cells. J Proteomics 103, 153–169.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, F., Wang, J., Wang, X., Wei, N., Liu, H., and Zhang, X. (2019). CD146-mediated acquisition of stemness phenotype enhances tumour invasion and metastasis after EGFR-TKI resistance in lung cancer. Clin Respir J 13, 23–33.

    Article  PubMed  Google Scholar 

  • Zhang, L., Luo, Y., Teng, X., Wu, Z., Li, M., Xu, D., Wang, Q., Wang, F., Feng, J., Zeng, X., et al. (2018). CD146: a potential therapeutic target for systemic sclerosis. Protein Cell 9, 1050–1054.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang, M., Yang, H., Wan, L., Wang, Z., Wang, H., Ge, C., Liu, Y., Hao, Y., Zhang, D., Shi, G., et al. (2020). Single-cell transcriptomic architecture and intercellular crosstalk of human intrahepatic cholangiocarcinoma. J Hepatol 73, 1118–1130.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, R., Chen, X., Chen, S., Tang, J., Chen, F., Lin, Y., Reinach, P.S., Yan, X., Tu, L. L., Duan, H., et al. (2022a). Inhibition of CD146 lessens uveal melanoma progression through reducing angiogenesis and vasculogenic mimicry. Cell Oncol 45, 557–572.

    Article  CAS  Google Scholar 

  • Zhang, T., Ma, C., Zhang, Z., Zhang, H., and Hu, H. (2021). NF-κB signaling in inflammation and cancer. MedComm 2, 618–653.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang, X., Wang, Z., Kang, Y., Li, X., Ma, X., and Ma, L. (2014). MCAM expression is associated with poor prognosis in non-small cell lung cancer. Clin Transl Oncol 16, 178–183.

    Article  CAS  PubMed  Google Scholar 

  • Zhang, Z.Y., Zhai, C., Yang, X.Y., Li, H.B., Wu, L.L., and Li, L. (2022b). Knockdown of CD146 promotes endothelial-to-mesenchymal transition via Wnt/β-catenin pathway. PLoS ONE 17, e0273542.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng, B., Ohuchida, K., Chijiiwa, Y., Zhao, M., Mizuuchi, Y., Cui, L., Horioka, K., Ohtsuka, T., Mizumoto, K., Oda, Y., et al. (2016). CD146 attenuation in cancer-associated fibroblasts promotes pancreatic cancer progression. Mol Carcinog 55, 1560–1572.

    Article  CAS  PubMed  Google Scholar 

  • Zheng, C., Qiu, Y., Zeng, Q., Zhang, Y., Lu, D., Yang, D., Feng, J., and Yan, X. (2009). Endothelial CD146 is required for in vitro tumor-induced angiogenesis: the role of a disulfide bond in signaling and dimerization. Int J Biochem Cell Biol 41, 2163–2172.

    Article  CAS  PubMed  Google Scholar 

  • Zhu, J. (2018). T helper cell differentiation, heterogeneity, and plasticity. Cold spring harb perspect biol 10, a030338.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zimmerlin, L., Donnenberg, V.S., Pfeifer, M.E., Meyer, E.M., Péault, B., Rubin, J.P., and Donnenberg, A.D. (2010). Stromal vascular progenitors in adult human adipose tissue. Cytometry Pt A 77A, 22–30.

    Article  CAS  Google Scholar 

  • Zou, Y., Lin, X., Bu, J., Lin, Z., Chen, Y., Qiu, Y., Mo, H., Tang, Y., Fang, W., and Wu, Z. (2020). Timeless-stimulated miR-5188-FOXO1/β-catenin-c-Jun feedback loop promotes stemness via ubiquitination of β-catenin in breast cancer. Mol Ther 28, 313–327.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

This work was supported In part by the Beijing Natural Science Foundation of China (L232077, 7242092, 7222117), the National Natural Science Foundation of China (82000812) and the China Postdoctoral Science Foundation (2023M733682).

Author information

Author notes

  1. Contributed equally to this work

Authors and Affiliations

  1. CAS Engineering Laboratory for Nanozyme, Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China

    Zhenzhen Wu, Yuzhe Zang, Chuyi Li, Zhiheng He, Jingyu Liu, Zhaoqi Du, Xinran Ma, Lin Jing, Hongxia Duan, Jing Feng & Xiyun Yan

  2. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China

    Yuzhe Zang, Chuyi Li, Zhiheng He, Jingyu Liu, Zhaoqi Du, Xinran Ma & Xiyun Yan

  3. Nanozyme Laboratory in Zhongyuan, Henan Academy of Innovations in Medical Science, Zhengzhou, 451163, China

    Hongxia Duan & Xiyun Yan

  4. Joint Laboratory of Nanozymes in Zhengzhou University, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China

    Xiyun Yan

Authors
  1. Zhenzhen Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuzhe Zang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chuyi Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhiheng He
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jingyu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhaoqi Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xinran Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lin Jing
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hongxia Duan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jing Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Xiyun Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Hongxia Duan, Jing Feng or Xiyun Yan.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, Z., Zang, Y., Li, C. et al. CD146, a therapeutic target involved in cell plasticity. Sci. China Life Sci. (2024). https://doi.org/10.1007/s11427-023-2521-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11427-023-2521-x

Search

Navigation