Abstract
Tetraspanin proteins form signaling complexes between them and with other membrane proteins and modulate cell adhesion and migration properties. The surface expression of several tetraspanin antigens (CD9, CD37, CD53, CD63, and CD81), and their interacting proteins (CD19, CD21, and HLA-DR) were analyzed during normal B-cell maturation and compared to a group of 67 B-cell neoplasias. Three patterns of tetraspanin expression were identified in normal B cells. The first corresponded to bone marrow CD10+ B-cell precursors (BCP) which showed high expression of CD81 and CD9, low reactivity for CD53 and negativity for CD37. CD10− B-lymphocytes showed downregulation of CD9/CD81 and upregulation of CD53/CD37. Plasma cells showed re-expressed CD9 and downregulated CD37. Hierarchical clustering analysis of flow cytometry immunophenotypic data showed a good correlation between the tumor differentiation stage and the pattern of tetraspanin expression, with all analyzed individual samples classified into three major groups, independently of their normal or neoplastic origin. Despite this, neoplastic B-cells frequently showed aberrantly high/low expression of the different markers analyzed. Interestingly, in B-cell chronic lymphocytic leukemia, abnormal expression of CD53 and CD9 were associated with different patterns of disease infiltration, which would support the role of these molecules on modulating adhesion and migration of neoplastic B cells.
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References
Masellis-Smith A, Jensen GS, Seehafer JG, Slupsky JR, Shaw AR . Anti-CD9 monoclonal antibodies induce homotypic adhesion of pre-B cell lines by a novel mechanism. J Immunol 1990; 144: 1607–1613.
Lazo PA, Cuevas L, Gutierrez del Arroyo A, Orue E . Ligation of CD53/OX44, a tetraspan antigen, induces homotypic adhesion mediated by specific cell–cell interactions. Cell Immunol 1997; 178: 132–140.
Cao L, Yoshino T, Kawasaki N, Sakuma I, Takahashi K, Akagi T . Anti-CD53 monoclonal antibody induced LFA-1/ICAM-1-dependent and -independent lymphocyte homotypic cell aggregation. Immunobiology 1997; 197: 70–81.
Levy S, Todd SC, Maecker HT . CD81 (TAPA-1): a molecule involved in signal transduction and cell adhesion in the immune system. Annu Rev Immunol 1998; 16: 89–109.
Shibagaki N, Hanada K, Yamashita H, Shimada S, Hamada H . Overexpression of CD82 on human T cells enhances LFA-1/ICAM-1-mediated cell-cell adhesion: functional association between CD82 and LFA-1 in T cell activation. Eur J Immunol 1999; 29: 4081–4091.
Lagaudriere-Gesbert C, Le Naour F, Lebel-Binay S, Billard M, Lemichez E, Boquet P et al. Functional analysis of four tetraspans, CD9, CD53, CD81, and CD82, suggests a common role in costimulation, cell adhesion, and migration: only CD9 upregulates HB-EGF activity. Cell Immunol 1997; 182: 105–112.
Yanez-Mo M, Alfranca A, Cabanas C, Marazuela M, Tejedor R, Ursa MA et al. Regulation of endothelial cell motility by complexes of tetraspan molecules CD81/TAPA-1 and CD151/PETA-3 with alpha3 beta1 integrin localized at endothelial lateral junctions. J Cell Biol 1998; 141: 791–804.
Miyake M, Nakano K, Ieki Y, Adachi M, Huang C, Itoi S et al. Motility related protein 1(MRP1/CD9) expression: inverse correlation with metastases in breast cancer. Cancer Res 1995; 55: 4127–4131.
Higashiyama M, Taki T, Ieki Y, Adachi M, Huang C, Koh T et al. Reduced motility related protein-1(MRP1/CD9) gene expression as a factor of poor prognosis in non-small cell lung cancer. Cancer Res 1995; 55: 6040–6044.
Longo N, Yanez-Mo M, Mittelbrunn M, de la Rosa G, Munoz ML, Sanchez-Madrid F et al. Regulatory role of tetraspanin CD9 in tumor-endothelial cell interaction during transendothelial invasion of melanoma cells. Blood 2001; 98: 3717–3726.
Zhang XA, Lane WS, Charrin S, Rubinstein E, Liu L . EWI2/PGRL associates with the metastasis suppressor KAI1/CD82 and inhibits the migration of prostate cancer cells. Cancer Res 2003; 63: 2665–2674.
Zhang XA, He B, Zhou B, Liu L . Requirement of the p130CAS-Crk coupling for metastasis suppressor KAI1/CD82-mediated inhibition of cell migration. J Biol Chem 2003; 278: 27319–27328.
Berditchevski F, Odintsova E . Characterization of integrin-tetraspanin adhesion complexes: role of tetraspanins in integrin signaling. J Cell Biol 1999; 146: 477–492.
Yanez-Mo M, Mittelbrunn M, Sanchez-Madrid F . Tetraspanins and intercellular interactions. Microcirculation 2001; 8: 153–168.
Hemler ME . Tetraspanin proteins mediate cellular penetration, invasion, and fusion events and define a novel type of membrane microdomain. Ann Rev Cell Dev Biol 2003; 19: 397–422.
Reid ME . Tetraspanin: red blood cells and beyond. Blood 2004; 104: 2211–2212.
Yunta M, Lazo PA . Apoptosis protection and survival signal by the CD53 tetraspanin antigen. Oncogene 2003; 22: 1219–1224.
Boucheix C, Rubinstein E . Tetraspanins. Cell Mol Life Sci 2001; 58: 1189–1205.
Boucheix C, Duc GHT, Jasmin C, Rubinstein E . Tetraspanins and malignancy. Exp Rev Mol Med 2001, 31 January:##http://www-ermm.cbcu.cam.ac.uk/01002381.htm.
Maecker HT, Todd SC, Levy S . The tetraspanin superfamily: molecular facilitators. FASEB J 1997; 11: 428–442.
Okochi H, Mine T, Nashiro K, Suzuki J, Fujita T, Furue M . Expression of tetraspans transmembrane family in the epithelium of the gastrointestinal tract. J Clin Gastroenterol 1999; 29: 63–67.
Berditchevski F . Complexes of tetraspanins with integrins: more than meets the eye. J Cell Sci 2001; 114: 4143–4151.
Yunta M, Lazo PA . Tetraspanin proteins as organisers of membrane microdomains and signalling complexes. Cell Signal 2003; 15: 559–564.
Tarrant JM, Robb L, van Spriel AB, Wright MD . Tetraspanins: molecular organisers of the leukocyte surface. Trends Immunol 2003; 24: 610–617.
Hemler ME . Integrin associated proteins. Current Biol 1998; 10: 578–585.
Hemler ME . Specific tetraspanin functions. J Cell Biol 2001; 155: 1103–1108.
Shaw AR, Domanska A, Mak A, Gilchrist A, Dobler K, Visser L et al. Ectopic expression of human and feline CD9 in a human B cell line confers beta 1 integrin-dependent motility on fibronectin and laminin substrates and enhanced tyrosine phosphorylation. J Biol Chem 1995; 270: 24092–24099.
Radford KJ, Thorne RF, Hersey P . CD63 associates with transmembrane 4 superfamily members, CD9 and CD81, and with B1 integrins in human melanoma. Biochem Biophys Res Commun 1996; 222: 13–18.
Rubinstein E, Poindessous-Jazat V, Le Naour F, Billard M, Boucheix C . CD9, but not other tetraspans, associates with the B1 integrin precursor. Eur J Immunol 1997; 27: 1919–1927.
Serru V, Le Naour F, Billard M, Azorsa DO, Lanza F, Boucheix C et al. Selective tetraspan–integrin complexes (CD81/alpha4beta1, CD151/alpha3beta1, CD151/alpha6beta1) under conditions disrupting tetraspan interactions. Biochem J 1999; 340 (Part 1): 103–111.
Szollosi J, Horejsi V, Bene L, Angelisova P, Damjanovich S . Supramolecular complexes of MHC class I, MHC class II, CD20, and tetraspan molecules (CD53, CD81, and CD82) at the surface of a B cell line JY. J Immunol 1996; 157: 2939–2946.
Kropshofer H, Spindeldreher S, Rohn TA, Platania N, Grygar C, Daniel N et al. Tetraspan microdomains distinct from lipid rafts enrich select peptide—MHC class II complexes. Nat Immunol 2002; 3: 61–68.
Engering A, Pieters J . Association of distinct tetraspanins with MHC class II molecules at different subcellular locations in human immature dendritic cells. Int Immunol 2001; 13: 127–134.
Sato S, Miller AS, Howard MC, Tedder TF . Regulation of B lymphocyte development and activation by the CD19/CD21/CD81/Leu 13 complex requires the cytoplasmic domain of CD19. J Immunol 1997; 159: 3278–3287.
Horvath G, Serru V, Clay D, Billard M, Boucheix C, Rubinstein E . CD19 is linked to the integrin-associated tetraspans CD9, CD81, and CD82. J Biol Chem 1998; 273: 30537–30543.
Iwata S, Kobayashi H, Miyake-Nishijima R, Sasaki T, Souta-Kuribara A, Nori M et al. Distinctive signaling pathways through CD82 and beta1 integrins in human T cells. Eur J Immunol 2002; 32: 1328–1337.
Puls KL, Hogquist KA, Reilly N, Wright MD . CD53, a thymocyte selection marker whose induction requires a lower affinity TCR-MHC interaction than CD69, but is up-regulated with slower kinetics. Int Immunol 2002; 14: 249–258.
Stipp CS, Orlicky D, Hemler ME . FPRP, a major, highly stoichiometric, highly specific CD81- and CD9- associated protein. J Biol Chem 2001; 276: 4853–4862.
Tedder TF, Inaoki M, Sato S . The CD19–CD21 complex regulates signal transduction thresholds governing humoral immunity and autoimmunity. Immunity 1997; 6: 107–118.
Vanderkerken K, Van Camp B, De Greef C, Vande Broek I, Asosingh K, Van Riet I . Homing of the myeloma cell clone. Acta Oncol 2000; 39: 771–776.
Testa JE, Brooks PC, Lin JM, Quigley JP . Eukaryotic expression cloning with an antimetastatic monoclonal antibody identifies a tetraspanin (PETA-3/CD151) as an effector of human tumor cell migration and metastasis. Cancer Res 1999; 59: 3812–3820.
Sordat I, Decraene C, Silvestre T, Petermann O, Auffray C, Pietu G et al. Complementary DNA arrays identify CD63 tetraspanin and alpha3 integrin chain as differentially expressed in low and high metastatic human colon carcinoma cells. Lab Invest 2002; 82: 1715–1724.
Hotta H, Ross AH, Huebner K, Isobe M, Wendeborn S, Chao MV et al. Molecular cloning and characterization of an antigen associated with early stages of melanoma tumor progression. Cancer Res 1988; 48: 2955–2962.
Kusukawa J, Ryu F, Kameyama T, Mekada E . Reduced expression of CD9 in oral squamous cell carcinoma: CD9 expression inversely related to high prevalence of lymph node metastasis. J Oral Pathol Med 2001; 30: 73–79.
Sauer G, Windisch J, Kurzeder C, Heilmann V, Kreienberg R, Deissler H . Progression of cervical carcinomas is associated with down-regulation of CD9 but strong local re-expression at sites of transendothelial invasion. Clin Cancer Res 2003; 9: 6426–6431.
Dong J, Lamb PW, Rinker-Schaeffer CW, Vukanovic J, Ichikawa T, Isaacs JT et al. KAI1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2. Science 1995; 268: 884–886.
Zhang XA, Kazarov AR, Yang X, Bontrager AL, Stipp CS, Hemler ME . Function of the tetraspanin CD151-alpha6beta1 integrin complex during cellular morphogenesis. Mol Biol Cell 2002; 13: 1–11.
Huang CI, Kohno N, Ogawa E, Adachi M, Taki T, Miyake M . Correlation of reduction in MRP-1/CD9 and KAI1/CD82 expression with recurrences in breast cancer patients. Am J Pathol 1998; 153: 973–983.
Adachi M, Taki T, Konishi T, Huang CI, Higashiyama M, Miyake M . Novel staging protocol for non-small-cell lung cancers according to MRP- 1/CD9 and KAI1/CD82 gene expression. J Clin Oncol 1998; 16: 1397–1406.
Ikeyama S, Koyama M, Yamaoko M, Sasada R, Miyake M . Suppression of cell motility and metastasis by transfection with human motility-related potein (MRP1/CD9) DNA. J Exp Med 1993; 177: 1231–1237.
Mollinedo F, Fontan G, Barasoain I, Lazo PA . Recurrent infectious diseases in human CD53 deficiency. Clin Diagn Lab Immunol 1997; 4: 229–231.
Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol 1999; 17: 3835–3849.
Bene MC, Castoldi G, Knapp W, Ludwig WD, Matutes E, Orfao A et al. Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL). Leukemia 1995; 9: 1783–1786.
Sanchez ML, Almeida J, Vidriales B, Lopez-Berges MC, Garcia-Marcos MA, Moro MJ et al. Incidence of phenotypic aberrations in a series of 467 patients with B chronic lymphoproliferative disorders: basis for the design of specific four-color stainings to be used for minimal residual disease investigation. Leukemia 2002; 16: 1460–1469.
Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403: 503–511.
Tibshirani R, Hastie T, Narasimhan B, Chu G . Diagnosis of multiple cancer types by shrunken centroids of gene expression. Proc Natl Acad Sci USA 2002; 99: 6567–6572.
Yanez-Mo M, Tejedor R, Rousselle P, Sanchez -Madrid F . Tetraspanins in intercellular adhesion of polarized epithelial cells: spatial and functional relationship to integrins and cadherins. J Cell Sci 2001; 114: 577–587.
Cook GA, Longhurst CM, Grgurevich S, Cholera S, Crossno Jr JT, Jennings LK . Identification of CD9 extracellular domains important in regulation of CHO cell adhesion to fibronectin and fibronectin pericellular matrix assembly. Blood 2002; 100: 4502–4511.
Le Naour F, Prenant M, Francastel C, Rubinstein E, Uzan G, Boucheix C . Transcriptional regulation of the human CD9 gene: characterization of the 5′-flanking region. Oncogene 1996; 13: 481–486.
Hernandez-Torres J, Yunta M, Lazo PA . Differential cooperation between regulatory sequences required for human CD53 gene expression. J Biol Chem 2001; 276: 35405–35413.
Higgins JP, Shinghal R, Gill H, Reese JH, Terris M, Cohen RJ et al. Gene expression patterns in renal cell carcinoma assessed by complementary DNA microarray. Am J Pathol 2003; 162: 925–932.
Lapointe J, Li C, Higgins JP, van de Rijn M, Bair E, Montgomery K et al. Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proc Natl Acad Sci 2004; 101: 811–816.
Martin-Martin B, Nabokina SM, Blasi J, Lazo PA, Mollinedo F . Involvement of SNAP-23 and syntaxin 6 in human neutrophil exocytosis. Blood 2000; 96: 2574–2583.
Mahmudi-Azer S, Downey GP, Moqbel R . Translocation of the tetraspanin CD63 in association with human eosinophil mediator release. Blood 2002; 99: 4039–4047.
Pérez-Andrés M, Almeida J, Martín-Ayuso M, Moro MJ, Martín-Núñez G, Galende J et al. Clonal plasma cells from monoclonal gammopathy of undetermined significance, multiple myeloma and plasma cell leucemia show different expresión profiles of molecules envolved in the interaction with the immunological bone marrow microenvironment. Leukemia 2005; in: press.
Lucio P, Parreira A, van den Beemd MW, van Lochem EG, van Wering ER, Baars E et al. Flow cytometric analysis of normal B cell differentiation: a frame of reference for the detection of minimal residual disease in precursor-B-ALL. Leukemia 1999; 13: 419–427.
Vidriales MB, Perez JJ, Lopez-Berges MC, Gutierrez N, Ciudad J, Lucio P et al. Minimal residual disease in adolescent (older than 14 years) and adult acute lymphoblastic leukemias: early immunophenotypic evaluation has high clinical value. Blood 2003; 101: 4695–4700.
Acknowledgements
This work was supported by grants from MEC SAF2004-02900 (PAL) and SAF 2002-03096 (AO), Fondo de Investigación Sanitaria PI02-0585 (PAL), Junta de Castilla y León SA01/04 and CSI18/03 (PAL), and Fundación Memoria Samuel Solórzano Barruso (PAL).
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Barrena, S., Almeida, J., Yunta, M. et al. Aberrant expression of tetraspanin molecules in B-cell chronic lymphoproliferative disorders and its correlation with normal B-cell maturation. Leukemia 19, 1376–1383 (2005). https://doi.org/10.1038/sj.leu.2403822
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DOI: https://doi.org/10.1038/sj.leu.2403822
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