Skip to main content

Advertisement

SpringerLink
Log in

The role of extracellular matrix metalloproteinase inducer protein in prostate cancer progression

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Extracellular matrix metalloproteinase inducer (EMMPRIN/CD147) is a multifunctional membrane glycoprotein overexpressed in many solid tumors, and involved in tumor invasion and angiogenesis. We investigated EMMPRIN expression in human prostate cancer (CaP) tissues and cells, and evaluated whether EMMPRIN expression is related to tumor progression and matrix metalloproteinase (MMPs) expression in human CaP. An immunohistochemical study using tissue microarrays of 120 primary CaPs of different grades and 20 matched lymph node metastases from untreated patients was performed. The association of EMMPRIN expression with clinicopathological parameters was evaluated. Co-immunolocalization for EMMPRIN and MMP-1, MMP-2 or MMP-9 in primary tumors was examined using confocal microscopy. Flow cytometry and immunoblotting were used to examine EMMPRIN expression in 11 metastatic CaP cell lines. Heterogeneous expression of EMMPRIN was found in 78/120 (65%) CaPs, correlated significantly with progression parameters including pre-treatment PSA level (P < 0.05) and increased with progression of CaP (Gleason score, P < 0.05; pathological stage, P < 0.01; nodal involvement, P < 0.05 and surgical margin, P < 0.05). Heterogeneous cytoplasmic MMP-1, MMP-2 and MMP-9 associated with EMMPRIN immunolabeling was observed, particularly in tumors with Gleason scores >3 + 4. Metastatic CaP cell lines, except DuCaP, expressed abundant EMMPRIN protein, indicating highly (∼45 to ∼65 kDa) and less (∼30 kDa) glycosylated forms, although with no relationship to cells being either androgen responsive or nonresponsive. Our results suggest that EMMPRIN may regulate MMPs and be involved in CaP progression, and as such, could provide a target for treating metastatic CaP disease.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Jian Y, Goldberg ID, Shi YE (2002) Complex roles of tissue inhibitors of metalloproteinases in cancer. Oncogene 21:2245–2252

    Article  Google Scholar 

  2. Egeblad M, Werb Z (2002) New function for the matrix metalloproteases in cancer progression. Nat Rev Cancer 2:163–176

    Article  CAS  Google Scholar 

  3. Martin MD, Matrisian LM (2007) The other side of MMPs: Protective roles in tumor progression. Cancer Metastasis Rev 26:717–724

    Article  PubMed  CAS  Google Scholar 

  4. MacDougall JR, Matrisian LM (1995) Contributions of tumor and stromal matrix metalloproteinases to tumor progression, invasion and metastasis. Cancer Metastasis Rev 14:351–362

    Article  PubMed  CAS  Google Scholar 

  5. Menashi S, Serova M, Ma L, Vignot S, Mourah S, Calvo F (2003) Regulation of extracellular matrix metalloproteinase inducer and matrix metalloproteinase expression by amphiregulin in transformed human breast epithelial cells. Cancer Res 63:7575–7580

    PubMed  CAS  Google Scholar 

  6. Toole BP (2003) Emmprin (CD147), a cell surface regulator of matrix metalloproteinase production and function. Curr Top Dev Biol 54:371–389

    Article  PubMed  CAS  Google Scholar 

  7. Yan L, Zucker S, Toole BP (2005) Roles of the multifunctional glycoprotein, emmprin (basigin; CD147), in tumor progression. Thromb Haemost 93:199–204

    PubMed  CAS  Google Scholar 

  8. Biswas C, Zhang Y, DeCastro R, Guo H, Nakamura T, Kataoka H, Nabeshima K (1995) The human tumor cell-derived collagenase stimulatory factor (renamed EMMPRIN) is a member of the immunoglobulin superfamily. Cancer Res 55:434–439

    PubMed  CAS  Google Scholar 

  9. Guo H, Majmudar G, Jensen TC, Biswas C, Toole BP, Gordon MK (1998) Characterization of the gene for human EMMPRIN, a tumor cell surface inducer of matrix metalloproteinases. Gene 220:99–108

    Article  PubMed  CAS  Google Scholar 

  10. Tang Y, Kesavan P, Nakada MT, Yan L (2004) Tumor-stroma interaction: positive feedback regulation of extracellular matrix metalloproteinase inducer (EMMPRIN) expression and matrix metalloproteinase-dependent generation of soluble EMMPRIN. Mol Cancer Res 2:73–80

    PubMed  CAS  Google Scholar 

  11. Caudroy S, Polette M, Nawrocki-Raby B, Cao J, Toole BP, Zucker S, Birembaut P (2002) EMMPRIN-mediated MMP regulation in tumor and endothelial cells. Clin Exp Metastasis 19:697–702

    Article  PubMed  CAS  Google Scholar 

  12. Tang Y, Nakada MT, Kesavan P, McCabe F, Millar H, Rafferty P, Bugelski P, Yan L (2005) Extracellular matrix metalloproteinase inducer stimulates tumor angiogenesis by elevating vascular endothelial cell growth factor and matrix metalloproteinases. Cancer Res 65:3193–3199

    PubMed  CAS  Google Scholar 

  13. Zucker S, Cao J, Chen WT (2000) Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatment. Oncogene 19:6642–6650

    Article  PubMed  CAS  Google Scholar 

  14. Zucker S, Hymowitz M, Rollo EE, Mann R, Conner CE, Cao J, Foda HD, Tompkins DC, Toole BP (2001) Tumorigenic potential of extracellular matrix metalloproteinase inducer. Am J Pathol 158:1921–1928

    PubMed  CAS  Google Scholar 

  15. Riethdorf S, Reimers N, Assmann V, Kornfeld JW, Terracciano L, Sauter G, Pantel K (2006) High incidence of EMMPRIN expression in human tumors. Int J Cancer 119:1800–1810

    Article  PubMed  CAS  Google Scholar 

  16. Tang W, Chang SB, Hemler ME (2004a) Links between CD147 function, glycosylation, and caveolin-1. Mol Biol Cell 15:4043–4050

    Article  PubMed  CAS  Google Scholar 

  17. Cozzi PJ, Wang J, Delprado W, Madigan MC, Fairy S, Russell PJ, Li Y (2006) Evaluation of urokinase plasminogen activator and its receptor in different grades of human prostate cancer. Human Pathol 37:1442–1451

    Article  CAS  Google Scholar 

  18. Cozzi PJ, Wang J, Delprado W, Perkins AC, Allen BJ, Russell PJ, Li Y (2005) MUC1, MUC2, MUC4, MUC5AC and MUC6 expression in the progression of prostate cancer. Clin Exp Metastasis 22:565–573

    Article  PubMed  CAS  Google Scholar 

  19. Rubin MA, Dunn R, Strawderman M, Pienta KJ (2002) Tissue microarray sampling strategy for prostate cancer biomarker analysis. Am J Surg Pathol 26:312–319

    Article  PubMed  Google Scholar 

  20. Thalmann GN, Anezinis PE, Chang SM, Zhau HE, Kim EE, Hopwood VL, Pathak S, von Eschenbach AC, Chung LW (1994) Androgen-independent cancer progression and bone metastasis in the LNCaP model of human prostate cancer. Cancer Res 54:2577–2581

    PubMed  CAS  Google Scholar 

  21. Gabison EE, Mourah S, Steinfels E, Yan L, Hoang-Xuan T, Watsky MA, De Wever B, Calvo F, Mauviel A, Menashi S (2005) Differential expression of extracellular matrix metalloproteinase inducer (CD147) in normal and ulcerated corneas: role in epithelio-stromal interactions and matrix metalloproteinase induction. Am J Pathol 166:209–219

    PubMed  CAS  Google Scholar 

  22. Nabeshima K, Iwasaki H, Koga K, Hojo H, Suzumiya J, Kikuchi M (2006) Emmprin (basigin/CD147): matrix metalloproteinase modulator and multifunctional cell recognition molecule that plays a critical role in cancer progression. Pathol Int 56:359–367

    Article  PubMed  CAS  Google Scholar 

  23. Davidson B, Givant-Horwitz V, Lazarovici P, Risberg B, Nesland JM, Trope CG, Schaefer E, Reich R (2003) Matrix metalloproteinases (MMP), EMMPRIN (extracellular matrix metalloproteinase inducer) and mitogen-activated protein kinases (MAPK): co-expression in metastatic serous ovarian carcinoma. Clin Exp Metastasis 20:621–631

    Article  PubMed  CAS  Google Scholar 

  24. Ishibashi Y, Matsumoto T, Niwa M, Suzuki Y, Omura N, Hanyu N, Nakada K, Yanaga K, Yamada K, Ohkawa K, Kawakami M, Urashima M (2004) CD147 and matrix metalloproteinase-2 protein expression as significant prognostic factors in esophogeal squamous cell carcinoma. Cancer 101:1994–2000

    Article  PubMed  CAS  Google Scholar 

  25. Marieb EA, Zoltan-Jones A, Li R, Misra S, Ghatak S, Cao J, Zucker S, Toole BP (2004) Emmprin promotes anchorage-independent growth in human mammary carcinoma cells by stimulating hyaluronan production. Cancer Res 64:1229–1232

    Article  PubMed  CAS  Google Scholar 

  26. Li HG, Xie DR, Shen XM, Li HH, Zeng H, Zeng YJ (2005) Clinicopathological significance of expression of paxillin, syndecan-1 and EMMPRIN in hepatocellular carcinoma. World J Gastroenterol 11:1445–1451

    PubMed  CAS  Google Scholar 

  27. Sier CF, Zuidwijk K, Zijlmans HJ, Hanemaaijer R, Mulder-Stapel AA, Prins FA, Dreef EJ, Kenter GG, Fleuren GJ, Gorter A (2006) EMMPRIN-induced MMP-2 activation cascade in human cervical squamous cell carcinoma. Int J Cancer 118:2991–2998

    Article  PubMed  CAS  Google Scholar 

  28. van der Jagt MF, Sweep FC, Waas ET, Hendriks T, Ruers TJ, Merry AH, Wobbes T, Span PN (2006) Correlation of reversion-inducing cysteine-rich protein with kazal motifs (RECK) and extracellular matrix metalloproteinase inducer (EMMPRIN), with MMP-2, MMP-9, and survival in colorectal cancer. Cancer Lett 237:289–297

    Article  PubMed  CAS  Google Scholar 

  29. Klein KA, Reiter RE, Redula J, Moradi H, Zhu XL, Brothman AR, Lamb DJ, Marcelli M, Belldegrun A, Witte ON, Sawyers CL (1997) Progression of metastatic human prostate cancer to androgen independence in immunodeficient SCID mice. Nat Med 3:402–408

    Article  PubMed  CAS  Google Scholar 

  30. Reimers N, Zafrakas K, Assmann V, Egen C, Riethdorf L, Riethdorf S, Berger J, Ebel S, Janicke F, Sauter G, Pantel K (2004) Expression of extracellular matrix metalloproteases inducer on micrometastatic and primary mammary carcinoma cells. Clin Cancer Res 10:3422–3428

    Article  PubMed  CAS  Google Scholar 

  31. Hugo H, Ackland ML, Blick T, Lawrence MG, Clements JA, Williams ED, Thompson EW (2007) Epithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression. J Cell Physiol 213:374–383

    Article  PubMed  CAS  Google Scholar 

  32. Kuphal S, Palm HG, Poser I, Bosserhoff AK (2005) Snail-regulated genes in malignant melanoma. Melanoma Res 15:305–313

    Article  PubMed  CAS  Google Scholar 

  33. Stetler-Stevenson WG, Yu AE (2001) Proteases in invasion: matrix metalloproteinases. Semin Cancer Biol 11:143–152

    Article  PubMed  CAS  Google Scholar 

  34. Pupa SM, Menard S, Forti S, Tagliabue E (2002) New insights into the role of extracellular matrix during tumor onset and progression. J Cell Physiol 192:259–267

    Article  PubMed  CAS  Google Scholar 

  35. Sun J, Hemler ME (2001) Regulation of MMP-1 and MMP-2 production through CD147/extracellular matrix metalloproteinase inducer interactions. Cancer Res 61:2276–2281

    PubMed  CAS  Google Scholar 

  36. Sidhu SS, Mengistab AT, Tauscher AN, LaVail J, Basbaum C (2004) The microvesicle as a vehicle for EMMPRIN in tumor-stromal interactions. Oncogene 23:956–963

    Article  PubMed  CAS  Google Scholar 

  37. Millimaggi D, Mari M, D’Ascenzo S, Carosa E, Jannini EA, Zucker S, Carta G, Pavan A, Dolo V (2007) Tumor vesicle-associated CD147 modulates the angiogenic capability of endothelial cells. Neoplasia 9:349–357

    Article  PubMed  CAS  Google Scholar 

  38. Pulukuri S, Patel J, Estes N, Rao JS (2007) Matrix metalloproteinase-1 (MMP-1) expression and biological significance in the progression of prostate cancer (abstract). In: American Association for Cancer Research Annual Meeting: proceedings, April 14–18, 2007, Los Angeles: AACR, 2007. Abstract nr 3072

  39. Gohji K, Fujimoto N, Hara I, Fujii A, Gotoh A, Okada H, Arakawa S, Kitazawa S, Miyake H, Kamidono S, Nakajima M (1998) Serum matrix metalloproteinase-2 and its density in men with prostate cancer as a new predictor of disease extension. Int J Cancer 79:96–101

    Article  PubMed  CAS  Google Scholar 

  40. Moses MA, Wiederschain D, Loughlin KR, Zurakowski D, Lamb CC, Freeman MR (1998) Increased incidence of matrix metalloproteinases in urine of cancer patients. Cancer Res 58:1395–1399

    PubMed  CAS  Google Scholar 

  41. Trudel D, Fradet Y, Meyer F, Harel F, Tetu B (2003) Significance of MMP-2 expression in prostate cancer: an immunohistochemical study. Cancer Res 63:8511–8515

    PubMed  CAS  Google Scholar 

  42. London CA, Sekhon HS, Arora V, Stein DA, Iversen PL, Devi GR (2003) A novel antisense inhibitor of MMP-9 attenuates angiogenesis, human prostate cancer cell invasion and tumorigenicity. Cancer Gene Ther 10:823–832

    Article  PubMed  CAS  Google Scholar 

  43. Sehgal G, Hua J, Bernhard EJ, Sehgal I, Thompson TC, Muschel RJ (1998) Requirement for matrix metalloproteinase-9 (gelatinase B) expression in metastasis by murine prostate carcinoma. Am J Pathol 152:591–596

    PubMed  CAS  Google Scholar 

  44. Wang L, Wu G, Yu L, Yuan J, Fang F, Zhai Z, Wang F, Wang H (2006) Inhibition of CD147 expression reduces tumor cell invasion in human prostate cancer cell line via RNA interference. Cancer Biol Ther 5:608–614

    Article  PubMed  CAS  Google Scholar 

  45. Tang W, Hemler ME (2004b) Caveolin-1 regulates matrix metalloproteinases-1 induction and CD147/EMMPRIN cell surface clustering. J Biol Chem 279:11112–11118

    Article  PubMed  CAS  Google Scholar 

  46. Yang JM, Xu Z, Wu H, Zhu H, Wu X, Hait WN (2003) Overexpression of extracellular matrix metalloproteinase in multidrug resistant cancer cells. Mol Cancer Res 1:420–427

    PubMed  CAS  Google Scholar 

  47. Li QQ, Wang WJ, Xu JD, Cao XX, Chen Q, Yang JM, Xu ZD (2007) Up-regulation of CD147 and matrix metalloproteinase-2, -9 induced by P-glycoprotein substrates in multidrug resistant breast cancer cells. Cancer Sci 98:1767–1774

    Article  PubMed  CAS  Google Scholar 

  48. Bramhall SR, Rosemurgy A, Brown PD, Bowry C, Buckels JA (2001) Marimastat Pancreatic Cancer Study Group. Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. J Clin Oncol 19:3447–3455

    PubMed  CAS  Google Scholar 

  49. Pavlaki M, Zucker S (2003) Matrix metalloproteinase inhibitors (MMPIs): the beginning of phase I or the termination of phase III clinical trials. Cancer Metastasis Rev 22:177–203

    Article  PubMed  CAS  Google Scholar 

  50. McCawley LJ, Crawford HC, King LE Jr, Mudgett J, Matrisian LM (2004) A protective role for matrix metalloproteinase-3 in squamous cell carcinoma. Cancer Res 64:6965–6972

    Article  PubMed  CAS  Google Scholar 

  51. Montel V, Kleeman J, Agarwal D, Spinella D, Kawai K, Tarin D (2004) Altered metastatic behaviour of human breast cancer cells after experimental manipulation of matrix metalloproteinase 8 gene expression. Cancer Res 64:1687–1694

    Article  PubMed  CAS  Google Scholar 

  52. Houghton AM, Grisolano JL, Baumann ML, Kobayashi DK, Hautamaki RD, Nehring LC, Cornelius LA, Shapiro SD (2006) Macrophage elastase (matrix metalloproteinase-12) suppresses growth of lung metastases. Cancer Res 66:6149–6155

    Article  PubMed  CAS  Google Scholar 

  53. Hess KR, Abbruzzese JL (2001) Matrix metalloproteinase inhibition of pancreatic cancer: matching mechanism of action to clinical trial design. J Clin Oncol 19:3445–3446

    PubMed  CAS  Google Scholar 

  54. Chen X, Su Y, Acuff H, Matrisian LM, Zent R, Pozzi A, Fingleton B (2005) Increased plasma MMP9 in integrin alpha1-null mice enhances lung metastasis of colon carcinoma cells. Int J Cancer 116:52–61

    Article  PubMed  CAS  Google Scholar 

  55. Xu J, Xu HY, Zhang Q, Song F, Jiang JL, Yang XM, Mi L, Wen N, Tian R, Wang L, Yao H, Feng Q, Zhang Y, Xing JL, Zhu P, Chen ZN (2007) HAb18G/CD147 functions in invasion and metastasis of hepatocellular carcinoma. Mol Cancer Res 5:605–614

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by US Department of Defence Prostate Cancer Research Program (New Investigator Award to YL, W81XWH-04-1-0048), Career Development Fellowship from Cancer Institute NSW Australia (YL) and Sydney Foundation for Medical Research (MCM).

Author information

Authors and Affiliations

  1. Discipline of Clinical Ophthalmology, Save Sight Institute, University of Sydney, GPO Box 4337, Sydney, NSW, 2001, Australia

    Michele C. Madigan

  2. Oncology Research Centre, Prince of Wales Hospital, Barker St, Randwick, NSW, 2031, Australia

    Elizabeth A. Kingsley & Pamela J. Russell

  3. Department of Surgery, St George Hospital, Gray Street, Kogarah, Sydney, NSW, 2217, Australia

    Paul J. Cozzi

  4. Department of Medicine, University of New South Wales, Kensington, Randwick, NSW, 2052, Australia

    Paul J. Cozzi, Pamela J. Russell & Yong Li

  5. Douglass Hanly Moir Pathology, North Ryde, Ryde, NSW, 2113, Australia

    Warick J. Delprado

  6. Cancer Care Centre, St George Hospital, Gray Street, Kogarah, Sydney, NSW, 2217, Australia

    Yong Li

Authors
  1. Michele C. Madigan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elizabeth A. Kingsley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paul J. Cozzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Warick J. Delprado
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pamela J. Russell
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Michele C. Madigan or Yong Li.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Madigan, M.C., Kingsley, E.A., Cozzi, P.J. et al. The role of extracellular matrix metalloproteinase inducer protein in prostate cancer progression. Cancer Immunol Immunother 57, 1367–1379 (2008). https://doi.org/10.1007/s00262-008-0473-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-008-0473-x

Keywords

Search

Navigation