Clinical Prospects of Matrix Metalloproteinases and Their Tissue Inhibitors Study in Ovarian Cancer Patients

E.S. Gershtein; N.V. Levkina; I.V. Tereshkina; V.D. Ermilova; N.D. Kushlinskii; Yu.V. Kruk; O.M. Kuznetsova; L.V. Adamyan; K.P. Laktionov

Clinical Prospects of Matrix Metalloproteinases and Their Tissue Inhibitors Study in Ovarian Cancer Patients

E.S. Gershtein¹, N.V. Levkina², I.V. Tereshkina³, V.D. Ermilova⁴, N.D. Kushlinskii⁵, Yu.V. Kruk⁶, O.M. Kuznetsova⁷, L.V. Adamyan⁸, K.P. Laktionov⁹

research article Pages: 27-36

¹ д.б.н., профессор, вед. науч. сотрудник, лаборатория клинической биохимии НИИ клинической онкологии, РОНЦ им. Н.Н.Блохина РАМН
² аспирант, хирургическое отделение опухолей женской репродуктивной системы НИИ клинической онкологии, РОНЦ им. Н.Н.Блохина РАМН
³ к.м.н., соискатель, кафедра клинической биохимии и лабораторной диагностики, ГБОУ ВПО «Московский государственный медико-стоматологический университет» (МГМСУ) Минздравсоцразвития России
⁴ к.м.н., вед. науч. сотрудник, отдел патологической анатомии опухолей человека НИИ клинической онкологии, РОНЦ им. Н.Н.Блохина РАМН
⁵ врач акушер-гинеколог, отделение комбинированных и комплексных методов лечения гинекологических заболеваний, ФГУ НЦ АГиП им. В.И.Кулакова Минздравсоцразвития России
⁶ к.м.н., соискатель, кафедра клинической биохимии и лабораторной диагностики, ГБОУ ВПО МГМСУ Минздравсоцразвития России
⁷ к.б.н., доцент, кафедра биохимии медицинского факультета, ГОУ ВПО «Российский университет дружбы народов»
⁸ академик РАМН, д.м.н., профессор, зам. директора по научной работе ФГУ НЦ АГиП им. В.И.Кулакова Минздравсоцразвития России
⁹ д.м.н., профессор, руководитель хирургического отделения опухолей женской репродуктивной системы НИИ клинической онкологии, РОНЦ им. Н.Н.Блохина РАМН

Keywords: матриксная металлопротеиназа 2 матриксная металлопротеиназа 7 матриксная металлопротеиназа 9 тканевой ингибитор матриксных металлопротеиназ 1 типа тканевой ингибитор матриксных металлопротеиназ 2 типа рак яичников диагностика прогноз

Abstract

Matrix metalloproteinase (MMP) 2, 7, 9 and their type 1 and 2 tissue inhibitors (TIMP) levels were measured with standard ELISA kits in tumor extracts, blood serum and ascitic fluid of patients with ovarian cancer, benign and borderline ovarian neoplasms - 49, 24 and 11 patients respectively. Significant increase of MMP-7 content was revealed in ovarian cancer tissue as compared to benign and borderlaine tumors. The same trend was demonstrated for MMP-9, while MMP-2 and TIMP-2 were significantly decreased in cancer tissue as compared to benign ovarian lesions, and TIMP-1 did not differ between various types of ovarian neoplasms.

Evaluation of the associations between the markers studied and clinico-pathologic features of ovarian cancer revealed no significant differences in MMPs levels depending on FIGO stage, but TIMP-1 level in stage III-IV tumors was significantly lower than in stage I-II (p=0.022). MMP-7 and MMP-2 levels were significantly higher in the tumors of patients with bilateral ovarian cancer than in those with unilateral lesion. No prominent associations with the character of ovarian cancer peritoneal dissemination, presence and size of metastases in greater omentum, as well as with the localization of distant metastases were found. All the markers were detected also in ascitic fluid. A negative association was revealed between the volume of ascites and its MMP-2 (R= -0.53; p=0.008) and TIMP-2 concentrations (R= -0.78; p=0.0002). And MMP-2 and MMP-7 concentrations in ascitic fluid were positively associated with corresponding tumor levels (R=0.55; p=0.013 and R=0.42; p=0.047 respectively).

Positive associations were also found between tumor and serum concentrations of MMP-2 (R=0.31, p=0.020), MMP-7 (R=0.29, p=0.006) and MMP-9 (R=0.24, p=0.019). A significant increase of serum levels was demonstrated for MMP-7 and MMP-9 in ovarian cancer as compared to benign tumor patients and control group of 30 practically healthy women. On the contrary, MMP-2 level in blood serum of ovarian cancer patients was decreased. Statistical evaluation revealed that MMP-7 can be regarded as the most notable serological marker for differential diagnostics of ovarian cancer. The sensitivity of this test in relation to control group comprised 78 % (cut-off - 4,67 ng/ml) at 95 % specificity level. Serum MMP-7 level also positively correlated with the key indices of ovarian cancer extension: disease stage, size of primary tumor, presence and character of peritoneal dissemination and metastases in greater omentum, presence and volume of ascites, as well as with classical ovarian cancer marker CA-125 level.

How to cite

Герштейн Е.С., Левкина Н.В., Терешкина И.В., Ермилова В.Д., Кушлинский Д.Н., Крюк Ю.В., Кузнецова О.М., Адамян Л.В., Лактионов К.П. Клинические перспективы исследования матриксных металлопротеиназ и их тканевых ингибиторов у больных раком яичников // Вопросы биологической, медицинской и фармацевтической химии. 2011. № 10. С. 27–36.

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Egeblad M., Werb Z. New functions for the matrix metalloproteinases in cancer progression // Nat. Rev. Cancer. 2002. V. 2. № 3. P. 161-174.
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[1] Герштейн Е.С., Талаева Ш.Ж., Сандыбаев М.Н., Кушлинский Н.Е. Клиническая роль системы активации плазминогена в опухолях человека // Молекулярная медицина. 2007. № 1. P. 4-8.

[2] Nelson A.R., Fingleton B., Rothenberg M.L., Matrisian L.M. Matrix metalloproteinases: biologic activity and clinical implications // J. Clin. Oncol. 2000. V. 18. № 5. P. 1135-1149.

[3] Deryugina E.I., Quigley J.P. Pleiotropic roles of matrix metalloproteinases in tumor angiogenesis: contrasting, overlapping and compensatory functions // Biochim. Biophys. Acta. 2010. V. 1803. № 1. P. 103-120.

[4] Egeblad M., Werb Z. New functions for the matrix metalloproteinases in cancer progression // Nat. Rev. Cancer. 2002. V. 2. № 3. P. 161-174.

[5] Visse R., Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: struc-ture, function, and biochemistry // Circ. Res. 2003. V. 92. № 8. P. 827-839.

[6] Tanimoto H., Underwood L.J., Shigemasa K. et al. The matrix me-talloprotease pump-1 (MMP-7, Matrilysin): A candidate marker/target for ovarian cancer detection and treatment // Tumour Biol. 1999. V. 20. № 2. P. 88-98.

[7] Wang F.Q., So J., Reierstad S., Fishman D.A. Matrilysin (MMP-7) promotes invasion of ovarian cancer cells by activation of progelatinase // Int. J. Cancer. 2005. V. 114. № 1. P. 19-31.

[8] Sillanpaa S., Anttila M., Suhonen K. et al. Prognostic significance of extracellular matrix metalloproteinase inducer and matrix metal-loproteinase 2 in epithelial ovarian cancer // Tumour Biol. 2007. V. 28. № 5. P. 280-289.

[9] Sillanpaa S., Anttila M., Voutilainen K. et al. Prognostic significance of matrix metalloproteinase-9 (MMP-9) in epithelial ovarian cancer // Gynecol. Oncol. 2007. V. 104. № 2. P. 296-303.

[10] Sillanpaa S.M., Anttila M.A., Voutilainen K.A. et al. Prognostic significance of matrix metalloproteinase-7 in epithelial ovarian cancer and its re-lation to beta-catenin expression // Int. J. Cancer. 2006. V. 119. № 8. P. 1792-1799.

[11] Torng P.L., Mao T.L., Chan W.Y. et al. Prognostic significance of stromal metallo-proteinase-2 in ovarian adenocarcinoma and its relation to carcinoma progression // Gynecol. Oncol. 2004. V. 92. № 2. P. 559-567.

[12] Demeter A., Sziller I., Csapo Z. et al. Molecular prognostic markers in recurrent and in non-recurrent epithelial ovarian cancer // Anticancer Res. 2005. V. 25. № 4. P. 2885-2889.

[13] Kenny H.A., Lengyel E. MMP-2 functions as an early response protein in ovarian cancer metastasis // Cell Cycle. 2009. V. 8. № 5. P. 683-688.

[14] Maatta M., Santala M., Soini Y. et al. Matrix metal-loproteinases 2 and 9 and their tissue inhibitors in low malignant potential ovarian tumors // Tumour Biol. 2004. V. 25. № 4. P. 188-192.

[15] Baker A.H., Edwards D.R., Murphy G. Metalloproteinase inhibitors: biological actions and thera-peutic opportunities // J. Cell Sci. 2002. V. 115. Pt. 19. P. 3719-3727.

[16] Goldman S., Shalev E. MMPS and TIMPS in ovarian physiology and pathophysiology // Front Biosci. 2004. V. 9. P. 2474-2483.

[17] Huang L.W., Garrett A.P., Bell D.A. et al. Differential expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 protein and mRNA in epithelial ovarian tumors // Gynecol. Oncol. 2000. V. 77. № 3. P. 369-376.

[18] Kamat A.A., Fletcher M., Gruman L.M. et al. The clinical relevance of stromal matrix metalloproteinase expression in ovarian cancer // Clin. Cancer. Res. 2006. V. 12. № 6. P. 1707-1714.

[19] Герштейн Е.С., Короткова Е.А., Щербаков А.М. и соавт. Матриксные металлопротеиназы 7 и 9 и их тканевые ингибиторы 1 и 4 типа в опухолях и плазме крови больных раком толстой кишки // Бюллетень экспериментальной биологической медицины. 2007. Т. 143. № 3. С. 438-441.

[20] Cai K.Q., Yang W.L., Capo-Chichi C.D. et al. Prominent ex-pression of metalloproteinases in early stages of ovarian tumorigenesis // Mol. Carcinog. 2007. V. 46. № 2. P. 130-143.

[21] Sakata K., Shigemasa K., Nagai N., Ohama K. Expression of matrix metalloproteinases (MMP-2, MMP-9, MT1-MMP) and their inhibitors (TIMP-1, TIMP-2) in common epithelial tumors of the ovary // Int. J. Oncol. 2000. V. 17. № 4. P. 673-681.

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