EXPRESSION OF MMP-9 AS A PROGNOSTIC FACTOR OF UTERINE SARCOMA


  • V.S. Sukhin Oncogynecological dept.
  • S.V. Danyliuk Pathomorphological lab.
  • О.М. Sukhina Radiation therapy dept., SI “Grigoriev Institute for Medical Radiology, NAMS of Ukraine”, Kharkiv, Ukraine
  • O.V. Sadniprjaniy Pathomorphological lab., Kherson regional oncological dispancery, Antonovka, Kherson region, Ukraine
  • D. Lindquist Radiation and Oncology Sciences dept., Umeå University, Umeå, Sweden
  • H. Hermelin Dept. of Pathology and Clinical Cytology, Central Hospital Falun, Sweden Falun, Sweden
  • M. Tarján Dept. of Pathology and Clinical Cytology, Central Hospital Falun, Sweden Falun, Sweden
Keywords: uterine sarcoma, MMP-9 expression, connection of MMP-9 expression and tumor progression, leiomyosarcoma, endometrial stromal sarcoma, undifferentiated uterine sarcoma

Abstract

Uterine sarcoma is a highly aggressive mesenchymal neoplasm with an extremely unfavorable prognosis. Up today there are still relevant issues concerning search for clinical-morphological and biomolecular criteria for prognosis relapse-free survival of uterine sarcoma patients. It is well-known, the increase of the expression level of MMP-9 in primary tumor or metastatic foci correlates with a low differentiation of tumor cells, high ability for invasiveness, high metastatic activity, and shortened life expectancy. It’s still unknown, whether it is possible to consider the expression of MMP-9 in uterine sarcoma cells as a convincing prognostic factor. For many types of epithelial malignant neoplasms, high metastatic rate is associated with an increase level of MMP-9 both in plasma and in tumor tissue. The purpose of this study is to investigate the features of MMP-9 expression in uterine sarcoma cells for development of the model for individual prediction of the disease course. The study of the surgical material of selected 54 cases of uterine sarcoma of stage I-II (according to FIGO criteria) with a known prognosis of the disease, which were distributed depending on the morphological type done: leiomyosarcoma (LMS) – 18 cases, endometrial stromal sarcoma (ESS) - 22 cases, undifferentiated sarcoma (US) – 14 (according to the classification of tumors of the uterus of the WHO). For histological examination, pieces of tissue were cut from different parts of the tumor nodes – central, peripheral, parts of the adjacent intact tissue of myometrium (total of 6-8 bits). The tumor cell phenotype was determined using low molecular weight cytokeratins (Cytokeratin PAN, AE1 / AE3), smooth muscle actin (Smooth Muscle Actin, 1A4), myogenin (Myogenin (F5D)), CD 10 and vimentin (Vimentin, V9). The histochemical label was evaluated in two parameters: the degree of prevalence and intensity of coloration. To assess the color intensity, a qualitative scale was used: 0 – no reaction, 1+ – weak cytoplasmic coloration to 30.0% of tumor cells, 2+ – moderate reaction, 30.0 to 60.0% of stained cells, 3+ – pronounced cytoplasmic reaction in 60,0-100,0% of tumor cells. Statistical processing of the data was performed using the “STATISTICA 10.0” program package. The conducted study has showed, the negative (0) and weak (1+) expression of matrix metalloproteinase-9 were observed in the most part of ESS and only partially in US. Despite the stage of the disease, with such a status of MMP-9, there was observed no signs of relapsed disease. The moderate (2+) and high (3+) expression of MMP-9 was detected in 44.5 % of uterine sarcoma, in the most part in LMS patients. However, if in LMS cases the progressive disease was observed only in one third of them (4 of 12 cases), in case of ESS and US, in all the patients with such tumors status there was observed relapsed disease. Such a reaction may be indicative for invasive and metastatic potential of ESS and US and cause of the hematogenous metastases.

References

[1] Abakumova, T. B., Gening, S. O., Dolgova, D. R., & Fomina, A. V. (2014). Matrix metalloproteinases in blood serum and neutrophil lysate for cervical cancer. Siberian Cancer Journal, 1, 18–25.

[2] Avtandilov, G. G. (2002). Fundamentals of quantitative pathological anatomy: [monograph]. M.: Medicine. ISBN 5-225-04151-5: 412.00 р.

[3] Anichkov, N. M., Kvetnoj, I. M., & Konovalov, S. S. (2004). Biology of tumor growth (molecular medical aspects). SPb.: “Publishing house “Prime EVROZNAK”. ISBN 5-94946-090-1

[4] Barinov, V. V., Knjazev, R. I., Bokin, I. I., & Mustafina, E. A. (2017). Matrix metalloproteinase 7 in uterine cancer (review). Oncogynecology, 7, 31–36. Retrieved from https://elibrary.ru/item.asp?id=28409047

[5] Berezhnaja, N. M., & Chehun, V. F. (2016). Physiological system of connective tissue and oncogenesis. І. The role of the cellular components of the stroma in tumor development. Oncology, 18(1), 4–14. Retrieved from http://nbuv.gov.ua/UJRN/OL_2016_18_1_3

[6] Berezhnaja, N. M., & Chehun, V. F. (2016). Physiological system of connective tissue and oncogenesis. ІІ. Extracellular matrix and metastasis. Oncology, 18(3), 164–176. Retrieved from www.oncology.kiev.ua/pdf/18_3/164.pdf

[7] Ganusevich, I. I. (2010). The role of matrix metalloproteinases (MMP) in malignant neoplasms. I. Characteristics of MMP, regulation of their activity, prognostic value. Oncology, 12(1), 10–16. Retrieved from http://dspace.nbuv.gov.ua/handle/123456789/19542

[8] Ganusevich, I. I. (2010). The role of matrix metalloproteinases (MMP) in malignant neoplasms. I. MMP involvement in angiogenesis, invasion and metastasis of tumors. Oncology, 12(2), 108–114. Retrieved from www.oncology.kiev.ua/pdf/44/108.pdf

[9] Gershtejn, E. S., & Kushlinskij, N. E. (2013). Clinical prospects of research of tumor-associated proteases and their tissue inhibitors in cancer patients. Bulletin of the RAMS, 5, 16–27. Retrieved from www.fesmu.ru/elib/Article.aspx?id=279067

[10] Dolzhikov, A. A., Churnosov, M. I., Pahomov, S. P., Orlova, V. S., Bykov, P. M., Muhina, T. S. … Altuhova, O. B. (2012). Molecular and genetic factors predicting smooth-muscle neoplasms of the uterus: the role of matrix metalloproteinases. Kursk Scientific and Practical Bulletin, 2, 138–146.

[11] Klisho, E. V., Kondakova, I. V., & Chojnzonov, E. L. (2003). Matrix metalloproteinases in oncogenesis. Siberian Cancer Journal, 2, 62–70. Retrieved from https://cyberleninka.ru/article/n/matriksnye-metalloproteinazy-v-onkogeneze

[12] Korolenkova, L. I., Stepanova, E. V., & Baryshnikov, A. Ju. (2011). Molecular and biological markers of adhesion, loss of intercellular connections, invasion and neoangiogenesis as factors of progression of cervical neoplasia and cervical cancer. Russian Biotherapeutic Journal, 10(2), 13–17. Retrieved from elibrary.ru/contents.asp?issueid=1111643

[13] Laktionov, K. P., Levkina, N. V., Kushlinskij, D. N., & Gershtejn, E. S. (2012). Study of matrix metalloproteinases and their tissue inhibitors in patients with ovarian neoplasms. Gynecology, 2, 48–54. Retrieved from https://doi.org/10.17650/1994-4098-2012-0-2-48-54

[14] Solov’eva, N. I., Timoshenko, O. S., Gureeva, T. A., & Kugaevskaja, E. V. (2015). Matrix metalloproteinases and their endogenous regulators for squamous cell carcinoma of the cervix: an overview of our own data. Biomedical Chemistry, 61(6), 694–704. DOI: 10.18097/PBMC20156106694

[15] Frank, G. A., Savchenko, V. G., Parovichnikova, E. N., Zavalishina, L. Je., & Gajdamaka, N. V. (2009). Importance of matrix metalloproteinases and their inhibitors in norm, oncology and oncohematology. Therapeutic archive, 7, 91–96. Retrieved from www.fesmu.ru/elib/Article.aspx?id=207120

[16] Ardi, V. C., Kupriyanova, T. A., Deryugina, E. I., & Quigley, J. P. (2007). Human neutrophils uniquely release TIMP-free MMP-9 to provide a potent catalytic stimulator of angiogenesis. Proc. Natl Acad. Sci. U.S.A., 104, 20262-20267. doi:10.1073/pnas.0706438104.

[17] Benassi, M. S., Gamberi, G., Magagnoli, G., Molendini, L., Ragazzini, P., Merli, M. ... Picci, P. (2001). Metalloproteinase expression and prognosis in soft tissue sarcomas. Annals of oncology, 12, 75–78.

[18] Bodner-Adler, B., Bodner, K., Kimberger, O., Czerwenka, K., Leodolter, S., & Mayerhofer, K. (2003). ММP-1 and ММP-2 expression in uterine leiomyosarcoma and correlation with different clinicopathologic parameters. J. Soc. Gynecol. Investig., 10(7), 443–446.

[19] Bodner-Adler, B., Bodner, K., Kimberger, O., Czerwenka, K., Leodolter, S., & Mayerhofer, K. (2004). Expression of matrix metalloproteinases in patients with uterine smooth muscle tumors: an immunohistochemical analysis of ММP-1 and ММP-2 protein expression in leiomyoma, uterine smooth muscle tumor of uncertain malignant potential, and leiomyosarcoma. J. Soc. Gynecol. Investig., 11(3), 182–186. doi: 10.1016/j.jsgi.2003.09.004.

[20] Bourboulia, D., & Stetler-Stevenson, W. G. (2010). Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): Positive and negative regulators in tumor cell adhesion. Seminars in Cancer Biology, 20, 161-168. doi:10.1016/j.semcancer.2010.05.002.

[21] Chiang, A. C., Massague, J. (2008). Molecular basis of metastasis. N. Engl. J. Med., 359, 2814–2823. doi: 10.1056/NEJMra0805239.

[22] Deryugina, E. I., Quigley, J. P. (2010). Pleiotropic roles of matrix metalloproteinases in tumor angiogenesis: contrasting, overlapping and compensatory functions. Biochim. Biophys. Acta., 1803 (1), 103-120. doi: 10.1016/j.bbamcr.2009.09.017.

[23] Figo committee on gynecologic oncology. (2009). FIGO staging for uterine sarcomas. Int. J. Gynaecol. Obstet., 104(3), 177-178. doi: 10.1016/j.ijgo.2008.12.008.

[24] Gadducci, A. (2011). Prognostic factors in uterine sarcoma. Best Prac. & Res. Clin. Obst. and Gyn., 25, 783–795. doi: 10.1016/j.bpobgyn.2011.06.002.

[25] Guo, X., Jo, V. Y., Mills, A. M., Zhu, S. X., Lee, C. H., Espinosa, I. … van de Rijn, M. (2015). Clinically Relevant Molecular Subtypes in Leiomyosarcoma. Clinical Cancer Res., 21(15), 3501-3511. doi: 10.1158/1078-0432.CCR-14-3141.

[26] Ii, M., Yamamoto, H., Adachi, Y., Maruyama, Y., & Shinomura, Y. (2006). Role of matrix metalloproteinase-7 (matrilysin) in human cancer invasion, apoptosis, growth, and angiogenesis. Experimental Biology Medicine, 231(1), 20–27. doi: 10.1177/153537020623100103.

[27] Jodele, S., Blavier, L., Yoon, J. M., & DeClerck, Y. A. (2006). Modifying the soil to affect the seed: role of stromal-derived matrix metalloproteinases in cancer progression. Cancer Metastasis Rev., 25, 35–43. doi: 10.1007/s10555-006-7887-8.

[28] Kessenbrock, K., Plaks, V., & Werb, Z. (2010). Matrix metalloproteinases: regulators of the tumor microenvironment. Cell., 141, 52–67. doi: 10.1016/j.cell.2010.03.015.

[29] Kurman, R. J., Carcangiu, M. L., Herrington, S., & Young, R. H. (2014). World Health Organization Classification of Tumours of the Female Reproductive Organs. IARC, Lyon., 307. ISBN-13 9789283224358.

[30] Minami, R., Tsunoda, H., Iijima, T., Yoshikawa, H., Nemori, R., & Noguchi, M. (2003). Early acquisition of gelatinolytic activity in carcinogenesis of the uterine. Mod. Pathology, 16(11), 1164–1170. doi: 10.1097/01.MP.0000094089.33691.60

[31] Nelson, C. M., & Bissell, M. J. (2006). Of extracellular matrix, scaffolds, and signaling: tissue architecture regulates development, homeostasis, and cancer. Ann. Rev. Cell. Dev. Biology, 22, 287–309. doi: 10.1146/annurev.cellbio.22.010305.104315

[32] Nucci, M. R. (2016). Practical issues related to uterine pathology: endometrial stromal tumors. Mod. Pathol., 29, 92–103. doi: 10.1038/modpathol.2015.140.

[33] Ravid, Y., Formanski, M., Smith, Y., Reich, R., & Davidson, B. (2016). Uterine leiomyosarcoma and endometrial stromal sarcoma have unique miRNA signatures. Gynecol. Oncology, 140(3), 512–517. doi: 10.1016/j.ygyno.2016.01.001.

[34] Ríos, I., Rovirosa, A., Morales, J., Gonzalez-Farre, B., Arenas, M., Ordi, J. ... Biete, A. (2014). Undifferentiated uterine sarcoma: a rare, not well known and aggressive disease: report of 13 cases. Arch Gynecol Obstet., 290(5), 993-997. doi: 10.1007/s00404-014-3311-8.

[35] Roebuck, M. M., Helliwell, T. R., Chaudhry, I. H., Kalogrianitis, S., Carter, S., Kemp, G. J. … Frostick, S. P. (2005). Matrix metalloproteinase expression is related to angiogenesis and histologic grade in spindle cell soft tissue neoplasms of the extremities. Am. J. Clin. Pathol., 123, 59–66. doi: 10.1309/lk1v-7r99-jl41-wvkp.

[36] Roy, R., Yang, J., & Moses, M. A. (2009). Matrix metalloproteinases as novel biomarkers and potential therapeutic targets in human cancer. J. Clin. Oncol., 27, 5287–5297. doi: 10.1200/JCO.2009.23.5556.

[37] Stetler-Stevenson, W. G. (2008). Tissue inhibitors of metalloproteinases in cell signaling: metalloproteinase-independent biological activities. Sci. Signal., 1, re6. doi: 10.1126/scisignal.127re6.

[38] Stetler-Stevenson, W. G., & Yu, A. E. (2001). Proteases in invasion: matrix metalloproteinases. Semin Cancer Biol., 11, 143–152. doi: 10.1006/scbi.2000.0365

[39] Sukhin, V. S. (2014). Surgical treatment of uterine sarcoma patients. Review. Women’s Health, 91(5), 46–49. Retrieved from www.med-expert.com.ua/download.php?file=http://med-expert.com.ua/wp...2014...

[40] Zhang, Y., Qian, H., Lin, C., Lang, J., Xiang, Y., Fu, M. … Liang, X. (2008). Adenovirus carrying ТІМP-3: a potential tool for cervical cancer treatment. Gynecol. Oncol., 108(1), 234–240. doi: 10.1016/j.ygyno.2007.09.033.
Published
2018-03-29
How to Cite
Sukhin, V., Danyliuk, S., SukhinaО., Sadniprjaniy, O., Lindquist, D., Hermelin, H., & Tarján, M. (2018). EXPRESSION OF MMP-9 AS A PROGNOSTIC FACTOR OF UTERINE SARCOMA. Reports of Morphology, 24(1), 21-27. https://doi.org/https://doi.org/10.31393/morphology-journal-2018-24(1)-04