Abstract
Matrix metalloproteinase 2 (MMP2) is important in breast cancer (BC) invasion and metastasis.
In order to study the expression of MMP2, in breast cancer brain metastasis, we used a syngeneic rat model of distant metastasis of ENU1564, a carcinogen-induced mammary adenocarcinoma cell line. At 6 weeks post left-ventricle inoculation we observed development of micro-metastasis in the brain. Immunohistochemistry (IHC) and Western blotting (WB) analyses showed that MMP2 protein expressions were significantly higher in neoplastic brain tissue compared to normal brain tissue. These results were confirmed by RT-PCR and gelatin zymography increased in MMP2 and activity in brain metastasis. The MMP2 mechanism of action in the brain is still under intense scrutiny. To study the role of MMP2 in the development of BC brain metastasis we transfected ENU1564 rat mammary adenocarcinoma cells with tissue inhibitor of MMP2 (TIMP2). Animals inoculated with ENU1564-TIMP2 cells had decreased orthotopic tumor growth, decreased orthotopic metastastic behavior and did not develop brain metastases. Mitogen activated protein kinase (MAPK) pathway components, such as ERK1/2, have been correlated to MMP expression and/or astrocyte activity. We found that BC brain metastases have peripheral astrocyte reactivity and higher expression of glial fibrillary acidic protein (GFAP) and phosphorylated-ERK1/2 (p-ERK1/2). Blockage of ERK1/2 phosphorylation by treatment with MEK inhibitor (PD98059) decreased the expression of MMP2 in cancer cells grown in rat astrocyte-conditioned media. Our results are highly suggestive that MMP2 plays a role in the development of BC metastases, in particular to the brain. Furthermore, our results suggest that astrocyte factors and the ERK1/2 signaling pathway may be associated with BC brain metastasis development; and that ERK1/2 may regulate MMP2 in a way that is modifiable by astrocyte factors.
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References
Alessandrini A (2002) The roles of map kinases in controlling cancer metastasis. In: Welch DR (ed) Cancer metastasis-related genes, V. 3, vol 20. Kluwer Academic, Boston, pp 35–51
Caudroy S, Polette M, Tournier JM, Burlet H, Toole B, Zucker S, Birembaut P (1999) Expression of the extracellular matrix metalloproteinase inducer (EMMPRIN) and the matrix metalloproteinase-2 in bronchopulmonary and breast lesions. J Histochem Cytochem 47:1575–1580
Danilewicz M, Sikorska B, Wagrowska-Danilewicz M (2003) Prognostic significance of the immunoexpression of matrix metalloproteinase MMP2 and its inhibitor TIMP2 in laryngeal cancer. Med Sci Monit 9:MT42–MT47
Dzwonek J, Rylski M, Kaczmarek L (2004) Matrix metalloproteinases and their endogenous inhibitors in neuronal physiology of the adult brain. FEBS Lett 567:129–135
Fujimake T, Price JE, Fan D, Bucana CD, Itoh K, Kirino T, Fidler IJ (1996) Selective growth of human melanoma cells in the brain parenchyma of nude mice. Melanoma Res 6:363–371
Gakiopoulou H, Nakopoulou L, Siatelis A (2003) Tissue inhibitor of metalloproteinase-2 as a multifunctional molecule of which the expression is associated with adverse prognosis of patients with urothelial bladder carcinomas. Clin Cancer Res 9:5573–5581
Hall DG, Stoica G (1994) Characterization of brain and bone-metastasizing clones selected from an ethylnitrosurea-induced rat mammary carcinoma. Clin Exp Metastasis 12:283–295
Hanemaaijer R, Verheijen JH, Maguire TM (2000) Increased gelatinase-A and gelatinase-B activities in malignant vs. benign breast tumors. Int J Cancer 86:204–207
Heppner KJ, Matrisian LM, Jensen RA, Rodgers WH (1996) Expression of most matrix metalloproteinase family members in breast cancer represents a tumor-induced host response. Am J Pathol 149:273–282
Hynes RO (2003) Metastatic potential: generic predisposition of the primary tumor or rare, metastatic variants-or both? Cell 113:821–823
Jones JL, Glynn P, Walker RA (1999) Expression of MMP-2 and MMP-9, their inhibitors, and the activator MT1-MMP in primary breast carcinomas. J Pathol 189:161–168
La Rocca G, Pucci-Minafra I, Marrazzo A, Taormina P, Minafra S (2004) Zymographic detection and clinical correlations of MMP-2 and MMP-9 in breast cancer sera. Br J Cancer 88:1318–1326
Lafleur MA, Tester AM, Thompson EW (2003) Selective involvement of TIMP-2 in the second activational cleavage of pro-MMP-2: refinement of the pro-MMP-2 activation mechanism. FEBS Lett 553:457–463
Le DM, Besson A, Fogg DK (2003) Exploitation of astrocytes by glioma cells to facilitate invasiveness: a mechanism involving matrix metalloproteinase-2 and the urokinase-type plasminogen activator-plasmin cascade. J Neurosci 23:4034–4043
Lebeau A, Nerlich AG, Sauer U, Lichtinghagen R, Lohrs U (1999) Tissue distribution of major matrix metalloproteinases and their transcripts in human breast carcinomas. Anticancer Res 19:4257–4264
Lee WJ, Shin CY, Yoo BK, Ryu JR, Choi EY, Cheong JH, Ryu JH, Ko KH (2003) Induction of matrix metalloproteinase-9 (MMP-9) in lipopolysaccharide- stimulated primary astrocytes is mediated by extracellular signal-regulated protein kinase 1/2 (Erk1/2). Glia 41:15–24
Leppa S, Saarto T, Vehmanen L, Blomqvist C, Elomaa I (2004) A high serum matrix metalloproteinase-2 level is associated with an adverse prognosis in node-positive breast carcinoma. Clin Cancer Res 10:1057–1063
Leveque T, Le Pavec G, Boutet A (2004) Differential regulation of gelatinase A and B and TIMP-1 and -2 by TNFalpha and HIV virions in astrocytes. Microbes Infect 6:157–163
Li H, Lindenmeyer F, Grenet C (2001) AdTIMP-2 inhibits tumor growth, angiogenesis, and metastases, and prolongs survival in mice. Hum Gene Ther 5:515–526
Liuzzi GM, Mastroianni CM, Latronico T (2004) Anti-HIV drugs decrease the expression of matrix metalloproteinases in astrocytes and microglia. Brain 127:398–407
Massengale JL, Gasche Y, Chan PH (2002) Carbohydrate source influences gelatinase production by mouse astrocytes in vitro. Glia 38:240–245
Mendes O, Kim HT, Stoica G (2005) Expression of MMP2, MMP9 and MMP3 in breast cancer brain metastasis in a rat model. Clin Exp Metastasis 22:237–246
Muir EM, Adcock KH, Morgenstern DA (2002) Matrix metalloproteases and their inhibitors are produced by overlapping populations of activated astrocytes. Brain Res Mol Brain Res 100:103–117
Nagashima G, Suzuki R, Asai J (2002) Immunohistochemical analysis of reactive astrocytes around glioblastoma: an immunohistochemical study of postmortem glioblastoma cases. Clin Neurol Neurosurg 104:125–131
Nie J, Pei D (2003) Direct activation of pro-matrix metalloproteinase-2 by leukolysin/membrane-type 6 matrix metalloproteinase/matrix metalloproteinase 25 at the asn(109)-Tyr bond. Cancer Res 63:6758–6762
Nishizuka I, Ishikawa T (2002) Analysis of gene expression involved in brain metastases from breast cancer using cDNA microarray. Breast Cancer 9:26–32
Ohshiba T, Miyaura C, Inada M, Ito A (2003) Role of RANKL-induced osteoclast formation and MMP-dependent matrix degradation in bone destruction by breast cancer metastasis. Cancer 90:1414–1421
Pan MR, Hung WC (2002) Nonsteroidal anti-inflammatory drugs inhibit matrix metalloproteinase-2 via suppression of the ERK/Sp1-mediated transcription. J Biol Chem 277:32775–32780
Remacle A, McCarthy K, Noel A (2000) High levels of TIMP-2 correlate with adverse prognosis in breast cancer. Int J Cancer 89:118–121
Scott KA, Holdsworth H, Balkwill FR, Dias S (2000) Exploiting changes in the tumour microenvironment with sequential cytokine and matrix metalloprotease inhibitor treatment 133 in a murine breast cancer model. Br J Cancer 83:1538–1543
Sierra A, Price JE, Garcia-Ramirez M (1997) Astrocyte-derived cytokines contribute to the metastatic brain specificity of breast cancer cells. Lab Invest 77:357–368
Somerville RP, Oblander SA, Apte SS (2003) Matrix metalloproteinases: old dogs with new tricks. Genome Biol 4:205–216
Stetler-Stevenson WG, Aznavoorian S, Liotta LA (1993) Tumor cell interactions with the extracellular matrix during invasion and metastasis. Annu Rev Cell Biol 9:541–573
Talvensaari-Mattila A, Paakko P, Turpeenniemi-Hujanen T (2003) Matrix metalloproteinase-2 (MMP-2) is associated with survival in breast carcinoma. Br J Cancer 89:1270–1275
Tester AM, Waltham M, Oh SJ, Bae SN, Bills MM, Walker EC, Kern FG, Stetler- Stevenson WG, Lippman ME, Thompson EW (2004) Pro-matrix metalloproteinase-2 transfection increases orthotopic primary growth and experimental metastasis of MDA-MB-231 human breast cancer cells in nude mice. Cancer Res 64:652–658
Yoneda T (2000) Cellular and molecular basis of preferential metastasis of breast cancer to bone. J Orthop Sci 5:75–81
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Stoica, G., Lungu, G. (2014). Role of MMP2 in Brain Metastasis. In: Hayat, M. (eds) Tumors of the Central Nervous System, Volume 13. Tumors of the Central Nervous System, vol 13. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7602-9_20
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DOI: https://doi.org/10.1007/978-94-007-7602-9_20
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