Imunomarcação de metaloproteinases 9 (MMP-9) e 2 (MMP-2) e seus inibidores (TIMP-1) e (TIMP-2) no tecido mamário canino normal e neoplásico

Hugo Henrique Ferreira; Denise Caroline Toledo; Adriana Marques Faria; Diego Pereira Araújo; Andrigo Barboza di Nardi; Regiani Nascimento Gagno Porto; Veridiana Maria Brianezi Dignani de Moura

doi:10.1590/1809-6891v21e-58640

Autores

Hugo Henrique Ferreira Universidade Federal de Goiás (UFG), Goiânia, Goiás, Brasil https://orcid.org/0000-0002-4431-9617
Denise Caroline Toledo Universidade Federal de Goiás (UFG), Goiânia, Goiás, Brasil https://orcid.org/0000-0001-9807-8495
Adriana Marques Faria Universidade Federal de Goiás (UFG), Goiânia, Goiás, Brasil https://orcid.org/0000-0002-8129-2476
Diego Pereira Araújo Universidade Federal de Goiás (UFG), Goiânia, Goiás, Brasil https://orcid.org/0000-0003-0986-6890
Andrigo Barboza di Nardi Universidade Estadual Paulista (UNESP), Jaboticabal, São Paulo, Brasil https://orcid.org/0000-0001-6463-2144
Regiani Nascimento Gagno Porto Universidade Federal de Goiás (UFG), Goiânia, Goiás, Brasil https://orcid.org/0000-0003-4640-3764
Veridiana Maria Brianezi Dignani de Moura Universidade Federal de Goiás (UFG), Goiânia, Goiás, Brasil https://orcid.org/0000-0001-7128-7035

DOI:

https://doi.org/10.1590/1809-6891v21e-58640

Resumo

Este estudo teve como objetivo realizar a imunomarcação de MMP-9 e MMP-2 e seus inibidores, TIMP-1 e TIMP-2, no tecido mamário canino normal e neoplásico, a fim de avaliar o comportamento dessas proteínas no remodelamento da matriz extracelular (MEC) em diferentes tipos neoplásicos mamários. Foram analisadas 48 amostras de tecido mamário canino, sendo 14 carcinomas complexos, 13 carcinomas tubulopapilares, seis de adenomas simples e 15 mamas sem alterações. Houve diferença em MMP-9, TIMP-1 e TIMP-2 de acordo com a histomorfologia mamária, sendo que MMP-9 apresentou maior imunoexpressão em células epiteliais e estromais em carcinomas tubulopapilares e complexos. TIMP-1 exibiu menor imunomarcação nas células estromais dos carcinomas complexos e TIMP-2 maior imunomarcação nas células epiteliais dos carcinomas tubulopapilares. Houve correlação positiva entre MMP-9 e TIMP-1 nas células epiteliais e estromais quanto à intensidade de imunomarcação e número de células marcadas na mama normal. Houve correlação positiva entre MMP-9 e TIMP-2 nas células epiteliais dos carcinomas tubulopapilares. Conclui-se que a atividade equilibrada entre MMP-9, MMP-2, TIMP-1 e TIMP-2 mantém a homeostase do tecido mamário canino normal enquanto a imunoexpressão aumentada de MMP-9 e TIMP-2 e a imunoexpressão reduzida de TIMP-1 nos carcinomas sugere condição propícia à evolução tumoral.
Palavras-chave: cão, glândula mamária, neoplasia, metaloproteinases de matriz.

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Referências

MOE L. Population-based incidence of mammary tumours in some dogs breeds. Journal Reprodutive Fertil Supplement. 2001; 57:439-443

Goldschmidt MH, Peña L, Zappulli V. Tumors of the Mammary Gland. In: Meuten, D. J. Tumors in Domestic Animals. 5º ed. Ames, John Wiley & Sons, Inc; 2017, cap. 17, p. 723-765

Massagué J, Obenauf AC. Metastatic Colonization. Nature. 2016; 529(7586):298-306

Willins AL, Sabeh F, Li X, Weiss SJ. Extracellular matrix determinants and the regulation of cancer cell invasion stratagems. Journal of Microscopy. 2013; 251(3):250-560. Disponível em: https://doi.org/10.1111/jmi.12064

» https://doi.org/10.1111/jmi.12064

Simpson CD, Anyiwe K, Schimmer AD. Anoikis resistance and tumor metastasis. Cancer lett. 2008; 272(2):177-85. Disponível em: https://doi.org/10.1016/j.canlet.2008.05.029

» https://doi.org/10.1016/j.canlet.2008.05.029

Kaushik S, Pickup MW, Weaver VM. From transformation to metastasis: deconstructing the extracellular matrix in breast câncer. Cancer Metastasis Rev. 2016; 35(4):655-667. Disponível em: https://doi.org/10.1007/s10555-016-9650-0

» https://doi.org/10.1007/s10555-016-9650-0

Kelley LC, Lohmer LL, Hagedorn EJ, Sherwood DR. Traversing the basement membrane in vivo: A diversity of strategies. J Cell Biol. 2014; 204(3):291-302. Disponível em: https://doi.org/10.1083/jcb.201311112

» https://doi.org/10.1083/jcb.201311112

Holanda AON, Oliveira ARS, Cruz KJC, Severo JS, Morais JBS, Silva BB, Marreiro DN. Zinc and metalloproteinases 2 and 9: What is their relation with breast cancer?. Rev. Assoc. Med. Bras. 2017; 63(1):78-84. Disponível em: https://doi.org/10.1590/1806-9282.63.01.78

» https://doi.org/10.1590/1806-9282.63.01.78

Davies KJ. The Complex Interaction of Matrix Metalloproteinases in the Migration of Cancer Cells through Breast Tissue Stroma. Int J Breast Cancer. 2014: 839094. Disponível em: http://dx.doi.org/10.1155/2014/839094

» http://dx.doi.org/10.1155/2014/839094

Groblewska M, Siewko M, Mroczko B, Szmitkowski M. The role of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in the development of esophageal cancer. Folia Histochem Cytobiol. 2012; 50(1):12-9

Jabłońska-Trypuć A, Matejczyk M, Rosochacki S. Matrix metalloproteinases (MMPs), the main extracellular matrix (ECM) enzymes in collagen degradation, as a target for anticancer drugs. J Enzyme Inhib Med Chem. 2016; 31(1):177-183. Disponível em: http:// http://dx.doi.org/10.3109/14756366.2016.1161620

» http://dx.doi.org/10.3109/14756366.2016.1161620

Radisky ES, Radisky DC. Matrix metalloproteinases as breast cancer drivers and therapeutic targets. Front Biosci (Landmark Ed). 2015; 20:1144-1163. Disponível em: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516284/

» https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516284

Bourboulia D, Stetler-Stevenson WG. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): Positive and negative regulators in tumor cell adhesion. Seminars in Cancer Biology. 2010; 20(3):161-168. Disponível em: https://doi.org/10.1016/j.semcancer.2010.05.002

» https://doi.org/10.1016/j.semcancer.2010.05.002

Kruidenier L, Macdonald TT, Collins JE, Pender SLF, Sanderson IR. Myofibroblast Matrix Metalloproteinases Activate the Neutrophil Chemoattractant CXCL7 From Intestinal Epithelial Cells. GASTROENTEROLOGY. 2006;130(1):127-136. Disponível em: https://doi.org/10.1053/j.gastro.2005.09.032

» https://doi.org/10.1053/j.gastro.2005.09.032

Solé S, Petegnief V, Gorina R, Chamorro A, Planas AM. Activation of Matrix Metalloproteinase-3 and Agrin Cleavage in Cerebral Ischemia/Reperfusion. Journal of Neuropathology and Experimental Neurology. 2004; 63(4): 338 349

Brew K, Nagase H. The tissue inhibitors of metalloproteinases (TIMPs): An ancient family with structural and functional diversity. Biochimica et Biophysica Acta. 2010; 803(1):55-7. Disponível em: https://doi.org/10.1016/j.bbamcr.2010.01.003

» https://doi.org/10.1016/j.bbamcr.2010.01.003

Jinga DC, Blidaru A, Condrea I, Ardeleanu C, Dragomir C, Stefanescu M, Matache C. MMP-9 and MMP-2 gelatinases and TIMP-1 and TIMP-2 inhibitors in breast cancer: correlations with prognostic factors. J Cell Mol Med. 2006; 10(2):499-510. Disponível em: https://doi.org/10.1111/j.1582-4934.2006.tb00415.x

» https://doi.org/10.1111/j.1582-4934.2006.tb00415.x

Li H, Qiu Z, Li F, Wang C. The relationship between MMP-2 and MMP-9 expression levels with breast cancer incidence and prognosis. Oncol Lett. 2017; 14(5):5865-5870. Disponível em: https://doi.org/10.3892/ol.2017.6924

» https://doi.org/10.3892/ol.2017.6924

Bonnans C, Chou J, Werb Z. Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol. 2014;15(12):786-801. Disponível em: https://doi.org/10.1038/nrm3904

» https://doi.org/10.1038/nrm3904

Yang B, Tang F, Zhang B, Zhao Y, Feng J, Rao Z. Matrix metalloproteinase-9 overexpression is closely related to poor prognosis in patients with colon câncer. World J Surg Oncol. 2014; 12(24):1-6. Disponível em: https://doi.org/10.1186/1477-7819-12-24

» https://doi.org/10.1186/1477-7819-12-24

Rojiani MV, Alidina J, Esposito N, Rojiani AM. Expression of MMP-2 correlates with increased angiogenesis in CNS metastasis of lung carcinoma. Int J Clin Exp Pathol. 2010;3(8):775-781. Disponível em: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2993228/

» https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2993228/

Manshadi ZD, Hamid M, Kosari F, Tayebinia H, Khodadadi I. The Relationship between Matrix Metalloproteinase Gene Polymorphisms and Tumor Type, Tumor Size, and Metastasis in Women with Breast Cancer in Central Iran. Middle East Journal of Cancer. 2018; 2(9):123-131.

Doyle DM, Miller KD. Development of new targeted therapies for breast cancer. Breast Cancer. 2008; 15(1):49-56. Disponível em: https://doi.org/10.1007/s12282-007-0003-2

» https://doi.org/10.1007/s12282-007-0003-2

Kawai K, Uetsuka K, Doi K, Nakayama H. The activity of matrix metalloproteinase (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in mammary tumors of dogs and rats. Journal of Veterinery Medical Science. 2006, 68(2):105-111

Hirayama K, Yokota H, Onai R, Kobayashi T, Kumata T, Kihara K, Okamoto M, Sako T, Nakade T, Izumisa Y, Taniyama H. Detection of matrix metalloproteinases in canine mammary tumours: analysis by immunohistochemistry and zymography. Journal of Comparative Pathology. 2002; 127:249-256. Disponível em: https://doi.org/10.1053/jcpa.2002.0590

» https://doi.org/10.1053/jcpa.2002.0590

Aresu L, Giantin M, Morello E, Vascellari M, Astagnaro M, Lopparelli R, Zancanella V, Granato A, Arico A, Bradaschia A, Mutinelli F, Dacasto M. Matrix metalloproteinases and their inhibitors in canine mammary tumors. BMC Vet Res. 2011; 7(33). Disponível em: https://doi.org/10.1186/1746-6148-7-33

» https://doi.org/10.1186/1746-6148-7-33

Wu ZS, Wu Q, Yang JH, Wang HQ, Ding XD, Yang F, Xu XC. Prognostic significance of MMP-9 and TIMP-1 serum and tissue expression in breast cancer. Int J Cancer. 2008; 122(9):2050-6. Disponível em: https://doi.org/10.1002/ijc.23337

» https://doi.org/10.1002/ijc.23337

Bubendorf L, Nocito A, Moch H, Sauter G. Tissue microarray (TMA) technology: miniaturized pathology archives for high-throughput in situ studies. Journal of Pathology. 2001; 195(1):72-79. Disponível em: https://doi.org/10.1002/path.893

» https://doi.org/10.1002/path.893

Majidinia M, Yousefi B. Breast tumor stroma: A driving force in the development of resistance to therapies. Chem Biol Drug Des. 2017; 89(3):309-318. Disponível em: https://doi.org/10.1111/cbdd.12893

» https://doi.org/10.1111/cbdd.12893

Khamis ZI, Sahab ZJ, Sang QA. Active Roles of Tumor Stroma in Breast Cancer Metastasis. Int J Breast Cancer. 2012: 574025. Disponivel em: http://dx.doi.org/10.1155/2012/574025

» http://dx.doi.org/10.1155/2012/574025

Kessenbrock K, Plaks V, Werb X. Matrix Metalloproteinases: Regulators of the Tumor Microenvironment. Cell. 2010; 141(1):52-67. Disponível em: https://doi.org/10.1016/j.cell.2010.03.015

» https://doi.org/10.1016/j.cell.2010.03.015

Loukopoulos P, Mungall BA, Straw RC, Thornton JR, Forbinson WF. Matrix Metalloproteinase-2 and -9 Involvement in Canine Tumors. Veterinary Pathology. 2003; 40(4):382-394. Disponível em: https://doi.org/10.1354/vp.40-4-382

» https://doi.org/10.1354/vp.40-4-382

Gramulia BC, Pulz LH, Mota EFF, Fukumasu H, Strefezzi RF. Matrix metalloproteinase 9 expression in canine mammary carcinomas. Brazilian Journal of Veterinary Pathology 2016; 9(2),:55 - 61

Pellikainen JM, Ropponen KM, Kataja VV, Kellokoski JK, Eskelinen MJ, Kosma VM. Expression of matrix metalloproteinase (MMP)-2 and MMP-9 in breast cancer with a special reference to activator protein-2, HER2, and prognosis. Clinical Cancer Research. 2004; 10(22):7621-7628. Disponível em: https://doi.org/10.1158/1078-0432.CCR-04-1061

» https://doi.org/10.1158/1078-0432.CCR-04-1061

Zhang X, Jin G, Li J, Zhang L. Association between Four MMP-9 Polymorphisms and Breast Cancer Risk: A Meta-Analysis. 2015. Medical science monitor : international medical journal of experimental and clinical research. 2015; 21:1115-1123. Disponível em: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413812/

» https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413812

Yousef EM, Tahir MR, Pierre-St Y, Gaboury LA. MMP-9 expression varies according to molecular subtypes of breast câncer. BMC Cancer 14. 2014; 609. Disponível em: https://doi.org/10.1186/1471-2407-14-609

» https://doi.org/10.1186/1471-2407-14-609

Scott K, Arnott C, Robinson S, Morre RJ, Thompson RG, Marshall JF, Balkwill FR. TNF-α regulates epithelial expression of MMP-9 and integrin αvβ6 during tumour promotion. A role for TNF-α in keratinocyte migration?. Oncogene 2004; 23; 6954-6966 (2004). Disponível em: https://doi.org/10.1038/sj.onc.1207915

» https://doi.org/10.1038/sj.onc.1207915

Festuccia C, Bologna M, Vicentini C, Tacconelli A, Miano R, Violini S, Mackay AR. Increased matrix metalloproteinase-9 secretion in short-term tissue cultures of prostatic tumor cells. International Jounal of Cancer. 1996; 69;386-393, Disponível em:

Papparella S, Restucci B, Paciello O, Maiolino P. Expression of matrix metalloprotease-2 (MMP-2) and the activator membrane type 1 (MT1- MMP) in canine mammary carcinomas. Journal of Comparative Pathology. 2002; 126(4):271-276. Disponível em: https://doi.org/10.1053/jcpa.2002.0552

» https://doi.org/10.1053/jcpa.2002.0552

Santos AA, Lopes CC, Ribeiro JR, Martins LR, Santos JC, Amorim IF, Gartner F, Matos AJ. Identification of prognostic factors in canine mammary malignant tumours: a multivariable survival study. BMC Veterinary Research 2013, 9(1):1-11. Disponível em: https://doi.org/10.1186/1746-6148-9-1

» https://doi.org/10.1186/1746-6148-9-1

Yokota H, Kumata T, Taketaba S, Kobayashi T, Moue H, Taniyama H, Hirayama K, Kagawa Y, Itoh N, Fujita O, Nakade T, Yuasa A. High expression of 92 kDa type IV collagenase (matrix metalloproteinase-9) in canine mammary adenocarcinoma. Biochimica et Biophysica Acta. 2001; 1568(1):7-12. Disponível em: https://doi.org/10.1016/S0304-4165(01)00192-1

» https://doi.org/10.1016/S0304-4165(01)00192-1

Nakopoulou L, Giannopoilou I, Lazaris AC, Alexandrou P, Tsirmpa I, Markaki S, Panayotopoulou E, Keramopoulos A. The favorable prognostic impact of tissue inhibitor of matrix metalloproteinases-1 protein overexpression in breast cancer cells. Acta Pathologica, Microbiologica et Immunologica Scandinavica. 2003; 111(11):1027-1036. Disponível em: https://doi.org/10.1111/j.1600-0463.2003.apm1111105.x

» https://doi.org/10.1111/j.1600-0463.2003.apm1111105.x

Wurtz SO, Schrohl AS, Sorensen NM, Lademann U, Christensen IJ, Mouridsen H, Brunner N. Tissue inhibitor of metalloproteinases-1 in breast cancer. Endocrine-Related Cancer. 2005, 12(2):215-227. Disponível em: https://doi.org/10.1677/erc.1.00719

» https://doi.org/10.1677/erc.1.00719

Vizoso FJ, González LO, Corte MD, Rodríguez JC, Vázquez J, Lamelas ML, Junquera S, Merino AM, García-Muñis JL. Study of matrix metalloproteinases and their inhibitors in breast cancer. British Journal of Cancer. 2007; 96(6):903-911. Disponível em: https://www.nature.com/articles/6603666

» https://www.nature.com/articles/6603666

Jobim FC, Xavier NL, Uchoa DM, Cruz DB, Saciloto M, Chemello N, Schwartsmann G. Prevalence of vascular-endothelial growth factor, matrix metalloproteinases and tissue inhibitors of metalloproteinases in primary breast cancer. Brazilian Journal of Medical and Biological Research. 2009; 42:979-987. Disponível em: http://dx.doi.org/10.1590/S0100-879X2009005000016

» http://dx.doi.org/10.1590/S0100-879X2009005000016

Têtu B, Brisson J, Wang CS, Lapointe H, Beaudry G, Blanchette C, Trudel D. The influence of MMP-14, TIMP-2 and MMP-2 expression on breast cancer prognosis. Breast Cancer Research. 2006; 8(3):1-28. Disponível em: https://doi.org/10.1186/bcr1503

» https://doi.org/10.1186/bcr1503