Skip to main content

Advertisement

Log in

Ecto-5′-nucleotidase promotes invasion, migration and adhesion of human breast cancer cells

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Associated with many molecules, metastasis includes cell adhesion to extracellular matrix, migration towards specific direction and invasion into local vessel of distant organs. The purpose of the present study was to evaluate the role of ecto-5′-nucleotidase (eN, ecto-5-NT, CD73) generated extracellular adenosine in biologically malignant behaviors of human breast cancer cell lines.

Materials and methods

Two human breast cancer cell lines, T-47D with lower expression of CD73 and MB-MDA-231 with higher expression of CD73, were used to investigate the functions of CD73. The effects of CD73 over-expression on invasion, migration and adhesion were observed in T-47D transfected with pcDNA-NT5E plasmid. The effects of specific CD73 inhibitor, α, ß-methylene ADP (APCP), were observed in MB-MDA-231 cells.

Results

The results showed CD-73 overexpression increased invasion, migration and adhesion to ECM of the pcDNA-NT5E transfected T-47D cells compared to the saline and mock vector controls. The increased cell mobility of CD-73-overexpressed T-47D cells was blocked by APCP. Adenosine increased the mobility of wild type T-47D cells. APCP inhibited the mobility of the MB-MDA-231 cells.

Conclusion

Taken together, our results indicated that CD73 may facilitate the adhesion, migration and invasion of human breast cancer cells through its enzyme activity of generating adenosine. This study provided a possibly molecular mechanism of metastasis of breast carcinoma.

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

Access this article

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

Similar content being viewed by others

References

  • Airas L, Salmi M, Jalkanen S (1993) Lymphocyte-vascular adhesion protein-2 is a novel 70-Kda molecule involved in lymphocyte adhesion to vascular endothelium. J Immunol 151:4228–4238

    PubMed  CAS  Google Scholar 

  • Airas L, Hellman J, Salmi M, Bono P, Puurunen T, Smith DJ, Jalkanen S (1995) Cd73 is involved in lymphocyte binding to the endothelium—characterization of lymphocyte vascular adhesion protein-2 identifies it as Cd73. J Exp Med 182:1603–1608

    Article  PubMed  CAS  Google Scholar 

  • Airas L, Niemela J, Jalkanen S (2000) CD73 engagement promotes lymphocyte binding to endothelial cells via a lymphocyte function-associated antigen-1-dependent mechanism. J Immunol 165:5411–5417

    PubMed  CAS  Google Scholar 

  • Arvilommi AM, Salmi M, Airas L, Kalimo K, Jalkanen S (1997) CD73 mediates lymphocyte binding to vascular endothelium in inflamed human skin. Eur J Immunol 27:248–254

    Article  PubMed  CAS  Google Scholar 

  • Bachmeier BE, Nerlich AG, Lichtinghagen R, Sommerhoff CP (2001) Matrix metalloproteinases (MMPs) in breast cancer cell lines of different tumorigenicity. Anticancer Res 21:3821–3828

    PubMed  CAS  Google Scholar 

  • Barcz E, Sommer E, Sokolnicka I, Gawrychowski K, Roszkowska-Purska K, Janik P, Skopinska-Rozewska E (1998) The influence of theobromine on angiogenic activity and proangiogenic cytokines production of human ovarian cancer cells. Oncol Rep 5:517–520

    PubMed  CAS  Google Scholar 

  • Blay J, White TD, Hoskin DW (1997) The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. Cancer Res 57:2602–2605

    PubMed  CAS  Google Scholar 

  • Canbolat O, Durak I, Cetin R, Kavutcu M, Demirci S, Ozturk S (1996) Activities of adenosine deaminase, 5′-nucleotidase, guanase, and cytidine deaminase enzymes in cancerous and non-cancerous human breast tissues. Breast Cancer Res Treat 37:189–193

    Article  PubMed  CAS  Google Scholar 

  • Cronstein BN (1994) Adenosine, an endogenous antiinflammatory agent. J Appl Physiol 76:5–13

    PubMed  CAS  Google Scholar 

  • Elvin P, Garner AP (2005) Tumour invasion and metastasis: challenges facing drug discovery. Curr Opinion Pharmacol 5:374–381

    Article  CAS  Google Scholar 

  • Eroglu A, Canbolat O, Demirci S, Kocaoglu H, Eryavuz Y, Akgul H (2000) Activities of adenosine deaminase and 5′ -nucleotidase in cancerous and noncancerous human colorectal tissues. Medical Oncology 17:319–324

    Article  PubMed  CAS  Google Scholar 

  • Fenoglio C, Necchi D, Civallero M, Ceroni M, Nano R (1997) Cytochemical demonstration of nitric oxide synthase and 5′nucleotidase in human glioblastoma. Anticancer Res 17:2507–2511

    PubMed  CAS  Google Scholar 

  • Fishman P, Bar-Yehuda S, Barer F, Madi L, Multani AS, Pathak S (2001) The A3 adenosine receptor as a new target for cancer therapy and chemoprotection. Exp Cell Res 269:230–236

    Article  PubMed  CAS  Google Scholar 

  • Gilles C, Bassuk JA, Pulyaeva H, Sage EH, Foidart JM, Thompson EW (1998) SPARC/osteonectin induces matrix metalloproteinase 2 activation in human breast cancer cell lines. Cancer Res 58:5529–5536

    PubMed  CAS  Google Scholar 

  • Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  PubMed  CAS  Google Scholar 

  • Kamath L, Meydani A, Foss F, Kuliopulos A (2001) Signaling from protease-activated receptor-1 inhibits migration and invasion of breast cancer cells. Cancer Res 61:5933–5940

    PubMed  CAS  Google Scholar 

  • Khoo HE, Ho CL, Chhatwal VJS, Chan STF, Ngoi SS, Moochhala SM (1996) Differential expression of adenosine A1 receptors in colorectal cancer and related mucosa. Cancer Lett 106:17–21

    Article  PubMed  CAS  Google Scholar 

  • Kondo T, Nakazawa T, Murata SI, Katoh R (2006) Expression of CD73 and its ecto-5′-nucleotidase activity are elevated in papillary thyroid carcinomas. Histopathology 48:612–614

    Article  PubMed  CAS  Google Scholar 

  • Lee H, Lin ECK, Liu LM, Smith JW (2003) Gene expression profiling of tumor xenografts: In vivo analysis of organ-specific metastasis. Int J Cancer 107:528–534

    Article  PubMed  CAS  Google Scholar 

  • Lelievre V, Muller JM, Falcon J (1998) Adenosine modulates cell proliferation in human colonic carcinoma. II. Differential behavior of HT29, DLD-1, Caco-2 and SW403 cell lines. Eur J Pharmacol 341:299–308

    Article  PubMed  CAS  Google Scholar 

  • Lennon PF, Taylor CT, Stahl GL, Colgan SP (1998) Neutrophil-derived 5 ′-adenosine monophosphate promotes endothelial barrier function via CD73-mediated conversion to adenosine and endothelial A(2B) receptor activation. J Exp Med 188:1433–1443

    Article  PubMed  CAS  Google Scholar 

  • Lu J, Pierron A, Ravid K (2003) An adenosine analogue, IB-MECA, down-regulates estrogen receptor a and suppresses human breast cancer cell proliferation. Cancer Res 63:6413–6423

    PubMed  CAS  Google Scholar 

  • Lutty GA, McLeod DS (2003) Retinal vascular development and oxygen-induced retinopathy: a role for adenosine. Prog Retin Eye Res 22:95–111

    Article  PubMed  CAS  Google Scholar 

  • Lutty GA, Mathews MK, Merges C, McLeod DS (1998) Adenosine stimulates canine retinal microvascular endothelial cell migration and tube formation. Curr Eye Res 17:594–607

    Article  PubMed  CAS  Google Scholar 

  • Madi L, Bar-Yehuda S, Barer F, Ardon E, Ochaion A, Fishman P (2003) A3 adenosine receptor activation in melanoma cells—association between receptor fate and tumor growth inhibition. J Biol Chem 278:42121–42130

    Article  PubMed  CAS  Google Scholar 

  • Manni A, Washington S, Griffith JW, Verderame MF, Mauger D, Demers LM, Samant RS, Welch DR (2002) Influence of polyamines on in vitro and in vivo features of aggressive and metastatic behavior by human breast cancer cells. Clin Exp Metastasis 19:95–105

    Article  PubMed  CAS  Google Scholar 

  • Merighi S, Mirandola P, Milani D, Varani K, Gessi S, Klotz KN, Leung E, Baraldi PG, Borea PA (2002) Adenosine receptors as mediators of both cell proliferation and cell death of cultured human melanoma cells. J Invest Dermatol 119:923–933

    Article  PubMed  CAS  Google Scholar 

  • Merighi S, Mirandola P, Varani K, Gessi S, Leung E, Baraldi PG, Tabrizi MA, Borea PA (2003) A glance at adenosine receptors: novel target for antitumor therapy. Pharmacol Ther 100:31–48

    Article  PubMed  CAS  Google Scholar 

  • Mujoomdar M, Bennett A, Hoskin D, Blay J (2004) Adenosine stimulation of proliferation of breast carcinoma cell lines: Evaluation of the [H-3]thymidine assay system and modulatory effects of the cellular microenvironment in vitro. J Cell Physiol 201:429–438

    Article  PubMed  CAS  Google Scholar 

  • Mullen P, Ritchie A, Langdon SP, Miller WR (1996) Effect of matrigel on the tumorigenicity of human breast and ovarian carcinoma cell lines. Int J Cancer 67:816–820

    Article  PubMed  CAS  Google Scholar 

  • Narravula S, Lennon PF, Mueller BU, Colgan SP (2000) Regulation of endothelial CD73 by adenosine: paracrine pathway for enhanced endothelial barrier functions. J Immunol 165:5262–5268

    PubMed  CAS  Google Scholar 

  • Natori Y, Baba T, Moriguchi M, Takeshita I, Fukui M (1992) Effects of Theophylline on the selective increases in intratumoral blood-flow induced by intracarotid infusion of adenosine and adenosine-triphosphate in C6 glioma-transplanted rat brains. Surg Neurol 37:8–14

    Article  PubMed  CAS  Google Scholar 

  • Okusa MD, Linden J, Huang LP, Rieger JM, Macdonald TL, Huynh LP (2000) A(2A) adenosine receptor-mediated inhibition of renal injury and neutrophil adhesion. Am Physiol Renal Physiol 279:F809-F818

    CAS  Google Scholar 

  • Panjehpour M, Castro M, Klotz KN (2005) Human breast cancer cell line MDA-MB-231 expresses endogenous A(2B) adenosine receptors mediating a Ca2+ signal. Br J Pharmacol 145:211–218

    Article  PubMed  CAS  Google Scholar 

  • Parr C, Jiang WG (2003) Quantitative analysis of lymphangiogenic markers in human colorectal cancer. Int J Oncol 23:533–539

    PubMed  CAS  Google Scholar 

  • Rathbone MP, Middlemiss PJ, Kim JK, Gysbers JW, Deforge SP, Smith RW, Hughes DW (1992) Adenosine and its nucleotides stimulate proliferation of chick astrocytes and human astrocytoma-cells. Neurosci Res 13:1–17

    Article  PubMed  CAS  Google Scholar 

  • Richard LF, Dahms TE, Webster RO (1998) Adenosine prevents permeability increase in oxidant-injured endothelial monolayers. Am J Physiol Heart Circ Physiol 43:H35–H42

    Google Scholar 

  • Sadej R, Spychala J, Skladanowski AC (2006) Expression of ecto-5′-nucleotidase (eN, CD73) in cell lines from various stages of human melanoma. Melanoma Res 16:213–222

    Article  PubMed  CAS  Google Scholar 

  • Schoen SW, Graeber MB, Toth L, Kreutzberg GW (1988) 5′-Nucleotidase in postnatal ontogeny of rat cerebellum: a marker for migrating nerve cells? Brain Res 467:125–136

    PubMed  CAS  Google Scholar 

  • Sitkovsky MV (2003) Use of the A(2A) adenosine receptor as a physiological immunosuppressor and to engineer inflammation in vivo. Biochem Pharmacol 65:493–501

    Article  PubMed  CAS  Google Scholar 

  • Sommers CL, Byers SW, Thompson EW, Torri JA, Gelmann EP (1994) Differentiation State and Invasiveness of Human Breast-Cancer Cell-Lines. Breast Cancer Res Treat 31:325–335

    Article  PubMed  CAS  Google Scholar 

  • Spychala J (2000) Tumor-promoting functions of adenosine. Pharmacol Ther 87:161–173

    Article  PubMed  CAS  Google Scholar 

  • Spychala J, Lazarowski E, Ostapkowicz A, Ayscue LH, Jin A, Mitchell BS (2004) Role of estrogen receptor in the regulation of ecto-5′-nucleotidase and adenosine in breast cancer. Clin Cancer Res 10:708–717

    Article  PubMed  CAS  Google Scholar 

  • Stochaj U, Dieckhoff J, Mollenhauer J, Cramer M, Mannherz HG (1989) Evidence for the direct interaction of chicken gizzard 5′-nucleotidase with laminin and fibronectin. Biochimica et Biophysica Acta 992:385–392

    PubMed  CAS  Google Scholar 

  • Su AI, Welsh JB, Sapinoso LM, Kern SG, Dimitrov P, Lapp H, Schultz PG, Powell SM, Moskaluk CA, Frierson HF, Hampton GM (2001) Molecular classification of human carcinomas by use of gene expression signatures. Cancer Res 61:7388–7393

    PubMed  CAS  Google Scholar 

  • Tey HB, Khoo HE, Tan CH (1992) Adenosine Modulates Cell-Growth in Human Epidermoid Carcinoma (a431) Cells. Biochem Biophys Res Commun 187:1486–1492

    Article  PubMed  CAS  Google Scholar 

  • Thompson EW, Paik SM, Brunner N, Sommers CL, Zugmaier G, Clarke R, Shima TB, Torri J, Donahue S, Lippman ME, Martin GR, Dickson RB (1992) Association of increased basement-membrane invasiveness with absence of estrogen-receptor and expression of vimentin in human breast-cancer cell-lines. J Cell Physiol 150:534–544

    Article  PubMed  CAS  Google Scholar 

  • Ujhazy P, Klobusicka M, Babusikova O, Strausbauch P, Mihich E, Ehrke MJ (1994) Ecto-5′-Nucleotidase (Cd73) in Multidrug-Resistant Cell-Lines Generated by Doxorubicin. International Journal of Cancer 59:83–93

    Article  CAS  Google Scholar 

  • Ujhazy P, Berleth ES, Pietkiewicz JM, Kitano H, Skaar JR, Ehrke MJ, Mihich E (1996) Evidence for the involvement of ecto-5′-nucleotidase (CD73) in drug resistance. International Journal of Cancer 68:493–500

    Article  CAS  Google Scholar 

  • Vogel M, Kowalewski HJ, Zimmermann H, Janetzko A, Margolis RU, Wollny HE (1991) Association of the Hnk-1 epitope with 5′-nucleotidase from torpedo-marmorata (electric ray) electric organ. Biochem J 278:199–202

    PubMed  CAS  Google Scholar 

  • Woodhouse EC, Amanatullah DF, Schetz JA, Liotta LA, Stracke ML, Clair T (1998) Adenosine receptor mediates motility in human melanoma cells. Biochem Biophys Res Commun 246:888–894

    Article  PubMed  CAS  Google Scholar 

  • Zajchowski DA, Bartholdi MF, Gong Y, Webster L, Liu HL, Munishkin A, Beauheim C, Harvey S, Ethier SP, Johnson PH (2001) Identification of gene expression profiles that predict the aggressive behavior of breast cancer cells. Cancer Res 61:5168–5178

    PubMed  CAS  Google Scholar 

  • Zernecke A, Bidzhekov K, Ozuyaman B, Fraemohs L, Liehn EA, Luscher-Firzlaff JM, Luscher B, Schrader J, Weber C (2006) CD73/Ecto-5 ′-nucleotidase protects against vascular inflammation and neointima formation. Circulation 113:2120–2127

    Article  PubMed  CAS  Google Scholar 

  • Zhou TT, Zhou P (2006) Crucial role for ecto-5′-nucleotidase(CD73) in invasion and migration of human breast cancer cell lines. Chin J Pathophysiol 22:360–364

    CAS  Google Scholar 

  • Zimmermann H (1992) 5′-nucleotidase—molecular-structure and functional-aspects. Biochem J 285:345–365

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Dr. Linda Thompson for providing pBluescript SK(+) plasmid.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ping Zhou.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, L., Zhou, X., Zhou, T. et al. Ecto-5′-nucleotidase promotes invasion, migration and adhesion of human breast cancer cells. J Cancer Res Clin Oncol 134, 365–372 (2008). https://doi.org/10.1007/s00432-007-0292-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-007-0292-z

Keywords

Navigation