The concentration of matrix metalloproteinase 9 in the tumor and peritumoral tissue as a prognostic marker in the breast cancer patients

Danijela M. Cvetković; Bojan Z. Milošević; Aleksandar M. Cvetković; Srdjan M. Ninković; Jovana V. Jovankić; Dalibor V. Jovanovic; Snežana D. Marković

doi:10.2298/VSP170313118C

Danijela M. Cvetković University of Kragujevac, Faculty of Science, Institute of Biology and Ecology, Kragujevac, Serbia
Bojan Z. Milošević University of Kragujevac, Faculty of Medical Sciences, Department of Surgery, Kragujevac, Serbia
Aleksandar M. Cvetković University of Kragujevac, Faculty of Medical Sciences, Department of Surgery, Kragujevac, Serbia
Srdjan M. Ninković University of Kragujevac, Faculty of Medical Sciences, Department of Surgery, Kragujevac, Serbia
Jovana V. Jovankić University of Kragujevac, Faculty of Medical Sciences, Department of Surgery, Kragujevac, Serbia
Dalibor V. Jovanovic University of Kragujevac, Faculty of Medical Sciences, Department of Pathology, Kragujevac, Serbia
Snežana D. Marković University of Kragujevac, Faculty of Science, Institute of Biology and Ecology, Kragujevac, Serbia

DOI: https://doi.org/10.2298/VSP170313118C

Keywords: breast neoplasms;, disease progression;, matrix metalloproteinase 9;, tissues.

Abstract

Background/Aim. Breast cancer is one of the most common malignancies among women all over the world. Tumor microenvironment represents one of the main regulators of tumorigenesis. We investigated the role of matrix metalloproteinases 9 (MMP-9) concentration in peritumoral tissue as a prognostic marker in the breast cancer patients. Methods. The ELISA test was used to determine a total MMP-9 concentration in carcinoma and peritumoral tissue sample in the patients with breast cancer. Comparison of MMP-9 protein expression with the clinicopathological parameters was evaluated. Results. Peritumoral tissue at 3 cm distance from the tumor produces more MMP-9 than the tumor itself. The ratio of concentrations of MMP-9 in the tumor and peritumoral tissue considerably changes in favor of peritumoral tissue with the increase of tumor size and the involvement of axillary lymph nodes. In N0 stage, the concentration ratio of MMP-9 in the tumor and peritumoral tissues was 1 : 1.44, but in the N2 stage, the ratio was 1 : 26.5. Conclusion. In patients with breast cancer even in an early stadium there is a change in MMP-9 concentration in peritumoral tissue. We can extract the group of patients at increased risk for the development of lymph node metastasis. A statistically significant difference between the concentrations of MMP-9 in the peritumoral tissue and cancer tissue exists only in case of metastatic disease not in MO stadium implying need for early detection of still unknown metastases in such patients.

Author Biographies

Danijela M. Cvetković, University of Kragujevac, Faculty of Science, Institute of Biology and Ecology, Kragujevac, Serbia

MSci

Bojan Z. Milošević, University of Kragujevac, Faculty of Medical Sciences, Department of Surgery, Kragujevac, Serbia

MD, MSci

Aleksandar M. Cvetković, University of Kragujevac, Faculty of Medical Sciences, Department of Surgery, Kragujevac, Serbia

MD, PhD

Srdjan M. Ninković, University of Kragujevac, Faculty of Medical Sciences, Department of Surgery, Kragujevac, Serbia

MD, PhD

Jovana V. Jovankić, University of Kragujevac, Faculty of Medical Sciences, Department of Surgery, Kragujevac, Serbia

Msci

Dalibor V. Jovanovic, University of Kragujevac, Faculty of Medical Sciences, Department of Pathology, Kragujevac, Serbia

Msci

Snežana D. Marković, University of Kragujevac, Faculty of Science, Institute of Biology and Ecology, Kragujevac, Serbia

Proffesor PhD

References

Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, et al. Bray Cancer incidence and mortality pat-terns in Europe: Estimates for 40 countries in 2012., Eur J Cancer 2013; 49: 1374–403.

Milijus D, Zivkovic S, Bozic Z. Cancer registry of central Serbia. Cancer incidence and mortality in Central Serbia 2012 Report 14. Belgrade: Institute of Public Health of Serbia “Dr Milan Jovanović Batut”; 2014.

Ławicki S, Głażewska EK, Sobolewska M, Będkowska GE, Szmitkowski M. Plasma Levels and Diagnostic Utility of Mac-rophage Colony-Stimulating Factor, Matrix Metalloprotein-ase-9, and Tissue Inhibitor of Metalloproteinases-1 as New Biomarkers of Breast Cancer. Ann Lab Med 2016; 36(3): 223–9.

Franco OE, Shaw AK, Strand DW, Hayward SW. Cancer associ-ated fibroblasts in cancer pathogenesis. Semin Cell Dev Biol 2010; 21(1): 33–9.

Lorusso G, Ruegg C.The tumor microenvironment and its con-tribution to tumor evolution toward metastasis. Histochem Cell Biol 2008; 130(6): 1091–103.

Taguchi A, Kawana K, Tomio K, Yamashita A, Isobe Y, Nagasaka K, et al. Matrix metalloproteinase (MMP)-9 in cancer-associated fibroblasts (CAFs) is suppressed by omega-3 poly-unsaturated fatty acids in vitro and in vivo. PLoS One 2014; 9(2): e89605.

Stuelten CH, Byfield SD, Arany PR, Karpova TS, Stetler-Stevenson W. Breast cancer cells induce stromal fibroblasts to express MMP-9 via secretion of TNF-α and TGF-β. 2005, J Cell Sc 2005; 118(Pt 10): 2143–53.

Psaila B, Lyden D. The metastatic niche: adapting the foreign soil. Nat Rev Cancer 2009; 9(4): 285–93.

Nieman KM, Romero IL, Van Houten B, Lengyel E. Adipose tis-sue and adipocytes support tumorigenesis and metastasis. Bio-chim Biophys Acta 2013; 1831(10): 1533–41.

Tabouret E, Bertucci F, Pierga JY, Petit T, Levy C, Ferrero JM, et al. MMP2 and MMP9 serum levels are associated with favora-ble outcome in patients with inflammatory breast cancer treated with bevacizumab-based neoadjuvant chemotherapy in the BEVERLY-2 study. Oncotarget 2016; 7(14): 18531–40.

Giganti MG, Tresoldi I, Sorge R, Melchiorri G, Triossi T, Masuelli L, et al. Physical exercise modulates the level of serum MMP-2 and MMP-9 in patients with breast cancer. Oncol Lett 2016; 12(3): 2119–26.

Wu QW, Yang QM, Huang YF, She HQ, Liang J, Yang QL, et al. Expression and clinical significance of matrix metallopro-teinase-9 in lymphatic invasiveness and metastasis of breast cancer. PLoS One 2014; 9(5): e97804.

Li Y, Jia Q, Wang Y, Li F, Jia Z, Wan Y. Rab40b upregulation correlates with the prognosis of gastric cancer by promoting migration, invasion, and metastasis. Med Oncol 2015; 32(4): 126.

Bjorklund M, Koivunen E. Gelatinase-mediated migration and invasion of cancer cells. Biochim Biophys Acta 2005; 1755(1): 37–69.

Yousef EM, Tahir MR, St-Pierre Y, Gaboury LA. MMP-9 ex-pression varies according to molecular subtypes of breast can-cer. BMC Cancer 2014; 14: 609.

Pellikainen JM, Ropponen KM, Kataja VV, Kellokoski JK, Es-kelinen MJ, Kosma VM. Expression of matrix metalloprotein-ase (MMP)-2 and MMP-9 in breast cancer with a special ref-erence to activator protein-2, HER2, and prognosis. Clin Cancer Res 2004; 10(22): 7621–8.

O-Charoenrat P, Rhys-Evans PH, Eccles SA. Expression of ma-trix metalloproteinases and their inhibitors correlates with in-vasion and metastasis in squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 2001; 127(7): 813–20.

Charous SJ, Stricklin GP, Nanney LB, Netterville JL, Burkey BB. Expression of matrix metalloproteinases and tissue inhibitor of metalloproteinases in head and neck squamous cell carci-noma. Ann Otol Rhinol Laryngol 1997; 106(4): 271–8.

Zhang B, Cao X, Liu Y, Cao W, Zhang F, Zhang S, et al. Tumor-derived matrix metalloproteinase-13 (MMP-13) correlates with poor prognoses of invasive breast cancer. BMC Cancer 2008; 8: 83.

Murawski M, Woźniak M, Duś-Szachniewicz K, Kołodziej P, Rzeszutko M, Ziółkowski P. Significance of Matrix Metallopro-teinase 9 Expression as Supporting Marker to Cytokeratin 19 mRNA in Sentinel Lymph Nodes in Breast Cancer Patients. Int J Mol Sci 2016; 17(4): pii: E571.

Song ZB, Ni JS, Wu P, Bao YL, Liu T, Li M, et al. Testes-specific protease 50 promotes cell invasion and metastasis by increasing NF-kappaB-dependent matrix metalloproteinase-9 expression. Cell Death Dis 201; 6(3): e1703.

Zeng Y, Liu C, Dong B, Li Y, Jiang B, Xu Y, et al. Inverse cor-relation between Naa10p and MMP-9 expression and the combined prognostic value in breast cancer patients. Med On-col 2013; 30(2): 562.

Zhao S, Ma W, Zhang M, Tang D, Shi Q, Xu S, et al. High ex-pression of CD147 and MMP-9 is correlated with poor prog-nosis of triple-negative breast cancer (TNBC) patients. Med Oncol 2013; 30(1): 335.

Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: ex-perience from a large study with long-term follow-up. Histo-pathology 1991; 19(5): 403–10.

Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 2010; 17(6): 1471–4.

Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein meas-urement with the Folin phenol reagent. J Biol Chem 1951; 193(1): 265–75.

Koepke J, Dresel M, Schmid S, Greulich T, Beutel B, Schmeck B, et al. Therapy with plasma purified alpha1-antitrypsin (Prolas-tin®) induces time-dependent changes in plasma levels of MMP-9 and MPO. PLoS One 2015; 10(1): e0117497.

Margonis GA, Buettner S, Sasaki K, Kim Y, Ratti F, Russolillo N, et al. The role of liver-directed surgery in patients with hepatic metastasis from primary breast cancer: a multi-institutional analysis. HPB (Oxford) 2016; 18(8): 700–5.

Khan SA, Amnekar R, Khade B, Barreto SG, Ramadwar M, Shrikhande SV, et al. p38-MAPK/MSK1-mediated overex-pression of histone H3 serine 10 phosphorylation defines dis-tance-dependent prognostic value of negative resection margin in gastric cancer. Clin Epigenetics 2016; 8: 88.

Uggeri F, Ronchi PA, Goffredo P, Garancini M, Degrate L, Nespoli L, et al. Metastatic liver disease from non-colorectal, non-neuroendocrine, non-sarcoma cancers: a systematic review. World J Surg Oncol 2015; 13: 191.

Seinen JM, Styring E, Verstappen V, Vult von Steyern F, Rydholm A, Suurmeijer AJ, et al. Radiation-associated angiosarcoma af-ter breast cancer: high recurrence rate and poor survival de-spite surgical treatment with R0 resection. Ann Surg Oncol 2012; 19(8): 2700–6.

Köhrmann A, Kammerer U, Kapp M, Dietl J, Anacker J. Expres-sion of matrix metalloproteinases (MMPs) in primary human breast cancer and breast cancer cell lines: New findings and review of the literature. BMC Cancer 2009; 9: 188.

Heo DS, Choi H, Yeom MY, Song BJ, Oh SJ. Serum levels of matrix metalloproteinase-9 predict lymph node metastasis in breast cancer patients. Oncol Rep 2014; 31(4): 1567–72.

Kousidou OC, Berdiaki A, Kletsas D, Zafiropoulos A, Theocharis AD, Tzanakakis GN, et al. Estradiol-estrogen receptor: a key interplay of the expression of syndecan-2 and metalloprotein-ase-9 in breast cancer cells. Mol Oncol 2008; 2(3): 223–32.

Momeny M, Saunus JM, Marturana F, McCart Reed AE, Black D, Sala G, et al. Heregulin-HER3-HER2 signaling promotes ma-trix metalloproteinase-dependent blood-brain-barrier transen-dothelial migration of human breast cancer cell lines. Onco-target 2015; 6(6): 3932–46.

Stark AM, Anuszkiewicz B, Mentlein R, Yoneda T, Mehdorn HM, Held-Feindt J. Differential expression of matrix metallopro-teinases in brain- and bone-seeking clones of metastatic MDA-MB-231 breast cancer cells. J Neurooncol 2007; 81(1): 39–48.

Daniele A, Zito AF, Giannelli G, Divella R, Asselti M, Mazzocca A, et al. Expression of metalloproteinases MMP-2 and MMP-9 in sentinel lymph node and serum of patients with metastat-ic and non-metastatic breast cancer. Anticancer Res 2010; 30(9): 3521–7.

Elkin M, Cohen I, Zcharia E, Orgel A, Guatta-Rangini Z, Peretz T, et al. Regulation of heparanase gene expression by estrogen in breast cancer. Cancer Res 2003; 63(24): 8821–6.

Nilsson UW, Garvin S, Dabrosin C. MMP-2 and MMP-9 activi-ty is regulated by estradiol and tamoxifen in cultured human breast cancer cells. Breast Cancer Res Treat 2007; 102(3): 253–61.

Losordo DW, Isner JM. Estrogen and angiogenesis: A review. Arterioscler Thromb Vasc Biol 2001; 21(1): 6–12.

Rashad YA, Elkhodary TR, El-Gayar AM, Eissa LA. Evalua-tion of Serum Levels of HER2, MMP-9, Nitric Oxide, and Total Antioxidant Capacity in Egyptian Breast Cancer Pa-tients: Correlation with Clinico-Pathological Parameters. Sci Pharm 2013; 82(1): 129–45.