Roles of the multifunctional glycoprotein, emmprin (basigin; CD147), in tumour progression

Summary

Emmprin (basigin;CD147) is a widely distributed cell surface glycoprotein that belongs to the Ig superfamily and is highly enriched on the surface of malignant tumour cells. Emmprin is involved in numerous physiological and pathological systems and exhibits several molecular and cellular characteristics, but a major function of emmprin is stimulation of synthesis of several matrix metalloproteinases. In tumours, emmprin most likely stimulates matrix metalloproteinase production in stromal fibroblasts and endothelial cells as well as in tumour cells themselves by a mechanism involving homophilic interactions between emmprin molecules on apposing cells or on neighbouring cells after membrane vesicle shedding. Membrane-associated cofactors, including caveolin-1 and annexin II, regulate emmprin activity. Emmprin induces angiogenesis via stimulation of VEGF production, invasiveness via stimulation of matrix metalloproteinase production and multidrug resistance via hyaluronan-mediated up-regulation of ErbB2 signaling and cell survival pathway activities. Although the detailed mechanisms whereby it regulates these numerous phenomena are not yet known, it is clear that emmprin is a major mediator of malignant cell behavior.

Keywords

Matrix metalloproteinases - angiogenesis - invasiveness - chemoresistance - tumour-stroma interaction

• References

• 1 Hanahan D, Weinberg RA. The hallmarks of cancer.. Cell 2000; 100: 57-70.
• 2 Biswas C, Zhang Y, DeCastro R. et al The human tumor cell-derived collagenase stimulatory factor (renamed EMMPRIN) is a member of the immunoglobulin superfamily.. Cancer Res 1995; 55: 434-9.
• 3 Koch C, Staffler G, Huttinger R. et al T cell activation- associated epitopes of CD147 in regulation of the T cell response, and their definition by antibody affinity and antigen density.. Int Immunol 1999; 11: 777-86.
• 4 Miyauchi T, Kanekura T, Yamaoka A. et al Basigin, a new, broadly distributed member of the immunoglobulin superfamily, has strong homology with both the immunoglobulin V domain and the beta-chain of major histocompatibility complex class II antigen.. J Biochem (Tokyo) 1990; 107: 316-23.
• 5 Fossum S, Mallett S, Barclay AN. The MRC OX-47 antigen is a member of the immunoglobulin superfamily with an unusual transmembrane sequence.. Eur J Immunol 1991; 21: 671-9.
• 6 Seulberger H, Lottspeich F, Risau W. The inducible blood--brain barrier specific molecule HT7 is a novel immunoglobulin-like cell surface glycoprotein.. Embo J 1990; 9: 2151-8.
• 7 Miyauchi T, Masuzawa Y, Muramatsu T. The basigin group of the immunoglobulin superfamily: complete conservation of a segment in and around transmembrane domains of human and mouse basigin and chicken HT7 antigen.. J Biochem (Tokyo) 1991; 110: 770-4.
• 8 Fan QW, Kadomatsu K, Uchimura K. et al Embigin/ basigin subgroup of the immunoglobulin superfamily: different modes of expression during mouse embryogenesis and correlated expression with carbohydrate antigenic markers.. Dev Growth Differ 1998; 40: 277-86.
• 9 Smalla KH, Matthies H, Langnase K. et al The synaptic glycoprotein neuroplastin is involved in longterm potentiation at hippocampal CA1 synapses.. Proc Natl Acad Sci U S A 2000; 97: 4327-32.
• 10 Hanna SM, Kirk P, Holt OJ. et al A novel form of the membrane protein CD147 that contains an extra Iglike domain and interacts homophilically.. BMC Biochem 2003; 4: 17
• 11 Biswas C. Tumor cell stimulation of collagenase production by fibroblasts.. Biochem Biophys Res Commun 1982; 109: 1026-34.
• 12 Biswas C. Collagenase stimulation in cocultures of human fibroblasts and human tumour cells.. Cancer Lett 1984; 24: 201-7.
• 13 Ellis SM, Nabeshima K, Biswas C. Monoclonal antibody preparation and purification of a tumor cell collagenase-stimulatory factor.. Cancer Res 1989; 49: 3385-91.
• 14 Basset P, Bellocq JP, Wolf C. et al A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinomas.. Nature 1990; 348: 699-704.
• 15 Hewitt R, Dano K. Stromal cell expression of components of matrix-degrading protease systems in human cancer.. Enzyme Protein 1996; 49: 163-73.
• 16 MacDougall JR, Matrisian LM. Contributions of tumour and stromal matrix metalloproteinases to tumor progression, invasion and metastasis.. Cancer Metastasis Rev 1995; 14: 351-62.
• 17 Biswas C, Nugent MA. Membrane association of collagenase stimulatory factor(s) from B-16 melanoma cells.. J Cell Biochem 1987; 35: 247-58.
• 18 Kataoka H, DeCastro R, Zucker S. et al Tumor cellderived collagenase-stimulatory factor increases expression of interstitial collagenase, stromelysin, and 72-kDa gelatinase.. Cancer Res 1993; 53: 3154-8.
• 19 Guo H, Zucker S, Gordon MK. et al Stimulation of matrix metalloproteinase production by recombinant extracellular matrix metalloproteinase inducer from transfected Chinese hamster ovary cells.. J Biol Chem 1997; 272: 24-7.
• 20 Sameshima T, Nabeshima K, Toole BP. et al Glioma cell extracellular matrix metalloproteinase inducer (EMMPRIN) (CD147) stimulates production of membrane- type matrix metalloproteinases and activated gelatinase A in co-cultures with brain- derived fibroblasts.. Cancer Lett 2000; 157: 177-84.
• 21 Kanekura T, Chen X, Kanzaki T. Basigin (CD147) is expressed on melanoma cells and induces tumor cell invasion by stimulating production of matrix metalloproteinases by fibroblasts.. Int J Cancer 2002; 99: 520-8.
• 22 Yang JM, Xu Z, Wu H. et al Overexpression of extracellular matrix metalloproteinase inducer in multidrug resistant cancer cells.. Mol Cancer Res 2003; 1: 420-7.
• 23 Tang Y, Kesavan P, Nakada MT. et al Tumor-stroma interaction: positive feedback regulation of extracellular matrix metalloproteinase inducer (EMMPRIN) expression and matrix metalloproteinase-dependent generation of soluble EMMPRIN.. Mol Cancer Res 2004; 2: 73-80.
• 24 Caudroy S, Polette M, Nawrocki-Raby B. et al Emmprin-mediated MMP regulation in tumor and endothelial cells.. Clin Exp Metastasis 2002; 19: 697-702.
• 25 DeCastro R, Zhang Y, Guo H. et al Human keratinocytes express emmprin, an extracellular matrix metalloproteinase inducer.. J Invest Dermatol 1996; 106: 1260-5.
• 26 Caudroy S, Polette M, Tournier JM. et al Expression of the extracellular matrix metalloproteinase inducer (EMMPRIN) and the matrix metalloproteinase- 2 in bronchopulmonary and breast lesions.. J Histochem Cytochem 1999; 47: 1575-80.
• 27 Li R, Huang L, Guo H. et al Basigin (murine EMMPRIN) stimulates matrix metalloproteinase production by fibroblasts.. J Cell Physiol 2001; 186: 371-9.
• 28 Seulberger H, Unger CM, Risau W. HT7, Neurothelin, Basigin, gp42 and OX-47--many names for one developmentally regulated immuno-globulin-like surface glycoprotein on blood-brain barrier endothelium, epithelial tissue barriers and neurons.. Neurosci Lett 1992; 140: 93-7.
• 29 Reed BH, Wilk R, Schock F. et al Integrin-dependent apposition of Drosophila extraembryonic membranes promotes morphogenesis and prevents anoikis.. Curr Biol 2004; 14: 372-80.
• 30 Sun J, Hemler ME. Regulation of MMP-1 and MMP-2 production through CD147/extracellular matrix metalloproteinase inducer interactions.. Cancer Res 2001; 61: 2276-81.
• 31 Nabeshima K, Suzumiya J, Nagano M. et al Emmprin, a cell surface inducer of matrix metalloproteinases (MMPs), is expressed in T-cell lymphomas.. J Pathol 2004; 202: 341-51.
• 32 Tang W, Chang SB, Hemler ME. Links between CD147 function, glycosylation, and caveolin-1.. Mol Biol Cell 2004; 15: 4043-50.
• 33 Yoshida S, Shibata M, Yamamoto S. et al Homooligomer formation by basigin, an immunoglobulin superfamily member, via its N-terminal immunoglobulin domain.. Eur J Biochem 2000; 267: 4372-80.
• 34 Berditchevski F, Chang S, Bodorova J. et al Generation of monoclonal antibodies to integrin-associated proteins. Evidence that alpha3beta1 complexes with EMMPRIN/basigin/OX47/M6.. J Biol Chem 1997; 272: 29174-80.
• 35 Tang W, Hemler ME. Caveolin-1 regulates matrix metalloproteinases-1 induction and CD147/EMMPRIN cell surface clustering.. J Biol Chem 2004; 279: 11112-8.
• 36 Ling Q, Jacovina AT, Deora A. et al Annexin II regulates fibrin homeostasis and neoangiogenesis in vivo.. J Clin Invest 2004; 113: 38-48.
• 37 Mai J, Finley Jr. RL, Waisman DM. et al Human procathepsin B interacts with the annexin II tetramer on the surface of tumor cells.. J Biol Chem 2000; 275: 12806-12.
• 38 Guo H, Li R, Zucker S. et al EMMPRIN (CD147), an inducer of matrix metalloproteinase synthesis, also binds interstitial collagenase to the tumor cell surface.. Cancer Res 2000; 60: 888-91.
• 39 Miyauchi T, Jimma F, Igakura T. et al Structure of the mouse basigin gene, a unique member of the immunoglobulin superfamily.. J Biochem (Tokyo) 1995; 118: 717-24.
• 40 Guo H, Majmudar G, Jensen TC. et al Characterization of the gene for human EMMPRIN, a tumor cell surface inducer of matrix metalloproteinases.. Gene 1998; 220: 99-108.
• 41 Liang L, Major T, Bocan T. Characterization of the promoter of human extracellular matrix metalloproteinase inducer (EMMPRIN).. Gene 2002; 282: 75-86.
• 42 Shi Y, Simmons MN, Seki T. et al Change in gene expression subsequent to induction of Pnn/DRS/ memA: increase in p21(cip1/waf1).. Oncogene 2001; 20: 4007-18.
• 43 Shi Y, Ouyang P, Sugrue SP. Characterization of the gene encoding pinin/DRS/memA and evidence for its potential tumor suppressor function.. Oncogene 2000; 19: 289-97.
• 44 Igakura T, Kadomatsu K, Taguchi O. et al Roles of basigin, a member of the immunoglobulin superfamily, in behavior as to an irritating odor, lymphocyte response, and blood-brain barrier.. Biochem Biophys Res Commun 1996; 224: 33-6.
• 45 Igakura T, Kadomatsu K, Kaname T. et al A null mutation in basigin, an immunoglobulin superfamily member, indicates its important roles in peri-implantation development and spermatogenesis.. Dev Biol 1998; 194: 152-65.
• 46 Philp NJ, Ochrietor JD, Rudoy C. et al Loss of MCT1, MCT3, and MCT4 expression in the retinal pigment epithelium and neural retina of the 5A11/basigin- null mouse.. Invest Ophthalmol Vis Sci 2003; 44: 1305-11.
• 47 Clamp MF, Ochrietor JD, Moroz TP. et al Developmental analyses of 5A11/Basigin, 5A11/Basigin-2 and their putative binding partner MCT1 in the mouse eye.. Exp Eye Res 2004; 78: 777-89.
• 48 Kirk P, Wilson MC, Heddle C. et al CD147 is tightly associated with lactate transporters MCT1 and MCT4 and facilitates their cell surface expression.. Embo J 2000; 19: 3896-904.
• 49 Wilson MC, Meredith D, Halestrap AP. Fluorescence resonance energy transfer studies on the interaction between the lactate transporter MCT1 and CD147 provide information on the topology and stoichiometry of the complex in situ.. J Biol Chem 2002; 277: 3666-72.
• 50 Cho JY, Fox DA, Horejsi V. et al The functional interactions between CD98, beta1-integrins, and CD147 in the induction of U937 homotypic aggregation.. Blood 2001; 98: 374-82.
• 51 Spring FA, Holmes CH, Simpson KL. et al The Oka blood group antigen is a marker for the M6 leukocyte activation antigen, the human homolog of OX-47 antigen, basigin and neurothelin, an immunoglobulin superfamily molecule that is widely expressed in human cells and tissues.. Eur J Immunol 1997; 27: 891-7.
• 52 Stonehouse TJ, Woodhead VE, Herridge PS. et al Molecular characterization of U937-dependent T-cell co-stimulation.. Immunology 1999; 96: 35-47.
• 53 Kasinrerk W, Tokrasinwit N, Phunpae P. CD147 monoclonal antibodies induce homotypic cell aggregation of monocytic cell line U937 via LFA-1/ICAM-1 pathway.. Immunology 1999; 96: 184-92.
• 54 Yurchenko V, Zybarth G, O'Connor M. et al Active site residues of cyclophilin A are crucial for its signaling activity via CD147.. J Biol Chem 2002; 277: 22959-65.
• 55 Pushkarsky T, Zybarth G, Dubrovsky L. et al CD147 facilitates HIV-1 infection by interacting with virus-associated cyclophilin A.. Proc Natl Acad Sci U S A 2001; 98: 6360-5.
• 56 Fadool JM, Linser PJ. 5A11 antigen is a cell recognition molecule which is involved in neuronal-glial interactions in avian neural retina.. Dev Dyn 1993; 196: 252-62.
• 57 Schlosshauer B. The blood-brain barrier: morphology, molecules, and neurothelin.. Bioessays 1993; 15: 341-6.
• 58 Sameshima T, Nabeshima K, Toole BP. et al Correlation of emmprin expression in vascular endothelial cells with blood-brain-barrier function: a study using magnetic resonance imaging enhanced by Gd-DTPA and immunohistochemistry in brain tumors.. Virchows Arch 2003; 442: 577-84.
• 59 Jiang JL, Zhou Q, Yu MK. et al The involvement of HAb18G/CD147 in regulation of store-operated calcium entry and metastasis of human hepatoma cells.. J Biol Chem 2001; 276: 46870-7.
• 60 Spinale FG, Coker ML, Heung LJ. et al A matrix metalloproteinase induction/activation system exists in the human left ventricular myocardium and is upregulated in heart failure.. Circulation 2000; 102: 1944-9.
• 61 Li YY, McTiernan CF, Feldman AM. Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling.. Cardiovasc Res 2000; 46: 214-24.
• 62 Konttinen YT, Li TF, Mandelin J. et al Increased expression of extracellular matrix metalloproteinase inducer in rheumatoid synovium.. Arthritis Rheum 2000; 43: 275-80.
• 63 Tomita T, Nakase T, Kaneko M. et al Expression of extracellular matrix metalloproteinase inducer and enhancement of the production of matrix metalloproteinases in rheumatoid arthritis.. Arthritis Rheum 2002; 46: 373-8.
• 64 Ibrahim SM, Koczan D, Thiesen HJ. Gene-expression profile of collagen-induced arthritis.. J Autoimmun 2002; 18: 159-67.
• 65 Foda HD, Rollo EE, Drews M. et al Ventilator-induced lung injury upregulates and activates gelatinases and EMMPRIN: attenuation by the synthetic matrix metalloproteinase inhibitor, Prinomastat (AG3340).. Am J Respir Cell Mol Biol 2001; 25: 717-24.
• 66 Haseneen NA, Vaday GG, Zucker S. et al Mechanical stretch induces MMP-2 release and activation in lung endothelium: role of EMMPRIN.. Am J Physiol Lung Cell Mol Physiol 2003; 284: L541-7.
• 67 Zucker S, Hymowitz M, Rollo EE. et al Tumorigenic potential of extracellular matrix metalloproteinase inducer (EMMPRIN).. Am J Pathol 2001; 158: 1921-8.
• 68 Jiang JL, Chan HC, Zhou Q. et al HAb18G/CD147-mediated calcium mobilization and hepatoma metastasis require both C-terminal and N-terminal domains.. Cell Mol Life Sci 2004; 61: 2083-91.
• 69 Tang Y, Kesavan P, McCabe F. et al A novel mechanism of tumor angiogenesis: EMMPRIN stimulates tumor angiogenesis by elevating VEGF and MMP, submitted for publication.
• 70 Basset P, Wolf C, Chambon P. Expression of the stromelysin-3 gene in fibroblastic cells of invasive carcinomas of the breast and other human tissues: a review.. Breast Cancer Res Treat 1993; 24: 185-93.
• 71 Okada A, Bellocq JP, Rouyer N. et al Membranetype matrix metalloproteinase (MT-MMP) gene is expressed in stromal cells of human colon, breast, and head and neck carcinomas.. Proc Natl Acad Sci U S A 1995; 92: 2730-4.
• 72 Majmudar G, Nelson BR, Jensen TC. et al Increased expression of stromelysin-3 in basal cell carcinomas.. Mol Carcinog 1994; 9: 17-23.
• 73 Polette M, Gilles C, Marchand V. et al Tumor collagenase stimulatory factor (TCSF) expression and localization in human lung and breast cancers.. J Histochem Cytochem 1997; 45: 703-9.
• 74 Muraoka K, Nabeshima K, Murayama T. et al Enhanced expression of a tumor-cell-derived collagenasestimulatory factor in urothelial carcinoma: its usefulness as a tumor marker for bladder cancers.. Int J Cancer 1993; 55: 19-26.
• 75 Javadpour N, Guirguis R. Tumor collagenasestimulating factor and tumor autocrine motility factor as tumor markers in bladder cancer--an update.. Eur Urol 1992; 21: 1-4.
• 76 Davidson B, Goldberg I, Berner A. et al EMMPRIN (extracellular matrix metalloproteinase inducer) is a novel marker of poor outcome in serous ovarian carcinoma.. Clin Exp Metastasis 2003; 20: 161-9.
• 77 Sameshima T, Nabeshima K, Toole BP. et al Expression of emmprin (CD147), a cell surface inducer of matrix metalloproteinases, in normal human brain and gliomas.. Int J Cancer 2000; 88: 21-7.
• 78 Dalberg K, Eriksson E, Enberg U. et al Gelatinase A, membrane type 1 matrix metalloproteinase, and extracellular matrix metalloproteinase inducer mRNA expression: correlation with invasive growth of breast cancer.. World J Surg 2000; 24: 334-40.
• 79 Nabeshima K, Lane WS, Biswas C. Partial sequencing and characterization of the tumor cell-derived collagenase stimulatory factor.. Arch Biochem Biophys 1991; 285: 90-6.
• 80 Taylor PM, Woodfield RJ, Hodgkin MN. et al Breast cancer cell-derived EMMPRIN stimulates fibroblast MMP2 release through a phospholipase A(2) and 5-lipoxygenase catalyzed pathway.. Oncogene 2002; 21: 5765-72.
• 81 Sidhu SS, Mengistab AT, Tauscher AN. et al The microvesicle as a vehicle for EMMPRIN in tumor-stromal interactions.. Oncogene 2004; 23: 956-63.
• 82 Vittorelli ML. Shed membrane vesicles and clustering of membrane-bound proteolytic enzymes.. Curr Top Dev Biol 2003; 54: 411-32.
• 83 Menashi S, Serova M, Ma L. et al Regulation of extracellular matrix metalloproteinase inducer and matrix metalloproteinase expression by amphiregulin in transformed human breast epithelial cells.. Cancer Res 2003; 63: 7575-7580.
• 84 Lim M, Martinez T, Jablons D. et al Tumor-derived EMMPRIN (extracellular matrix metalloproteinase inducer) stimulates collagenase transcription through MAPK p38.. FEBS Lett 1998; 441: 88-92.
• 85 Marieb EA, Zoltan-Jones A, Li R. et al Emmprin promotes anchorage-independent growth in human mammary carcinoma cells by stimulating hyaluronan production.. Cancer Res 2004; 64: 1229-32.
• 86 Misra S, Ghatak S, Zoltan-Jones A. et al Regulation of multi-drug resistance in cancer cells by hyaluronan.. J Biol Chem 2003; 278: 25285-8.
• 87 Toole BP. Hyaluronan: from extracellular glue to pericellular cue.. Nat Rev Cancer 2004; 4: 528-39.
• 88 Zoltan-Jones A, Huang L, Ghatak S. et al Elevated hyaluronan production induces mesenchymal and transformed properties in epithelial cells.. J Biol Chem 2003; 278: 45801-10.
• 89 Reimers N, Zafrakas K, Assmann V. et al Expression of extracellular matrix metalloproteases inducer on micrometastatic and primary mammary carcinoma cells.. Clin Cancer Res 2004; 10: 3422-8.
• 90 Klein CA, Seidl S, Petat-Dutter K. et al Combined transcriptome and genome analysis of single micrometastatic cells.. Nat Biotechnol 2002; 20: 387-92.