Альманах клинической медицины. 2017; 45: 94-101
Матриксные металлопротеиназы-2, 7, 8, 9 и их тканевой ингибитор 1-го типа в сыворотке крови больных раком почки: клинико-морфологические корреляции
https://doi.org/10.18786/2072-0505-2017-45-2-94-101Аннотация
Актуальность. Причиной поздней диагностики рака почки считается долгое практически бессимптомное течение заболевания. Успехи в его лечении, достигнутые в последние годы, обусловлены использованием антиангиогенных препаратов. Тем не менее многие вопросы диагностики, прогноза и предсказания эффективности таргетной терапии до сих пор не решены. Таким образом, изучение и поиск новых молекулярных маркеров рака почки, в первую очередь показателей, связанных с ангиогенной и инвазивной активностью, по-прежнему актуальны. К таким маркерам относятся матриксные металлопротеиназы (ММП), разрушающие большинство компонентов внеклеточного матрикса и вовлеченные во все этапы опухолевого процесса. Цель – сравнительная оценка содержания ММП-2, 7, 8, 9 и их тканевого ингибитора 1-го типа (ТИМП-1) в сыворотке крови практически здоровых людей, больных раком и доброкачественными опухолями почки, анализ их взаимосвязи с основными клинико-морфологическими особенностями новообразований. Материал и методы. Обследованы 99 больных раком почки (94 первичных и 5 – на фоне прогрессирования) и 10 больных доброкачественными опухолями почки. В контрольную группу вошли 97 человек. Концентрацию исследуемых белков в сыворотке крови определяли с помощью наборов реактивов для прямого иммуноферментного анализа (Quantikine®, R&D Systems, США). Результаты. Содержание ММП-7, ММП-8 и ТИМП-1 в сыворотке крови больных раком почки статистически значимо выше, чем в контроле и у больных доброкачественными опухолями. Содержание ММП-2 и ММП-9 достоверно не различалось между обследованными группами. При пороговом уровне ММП-7, равном 3,0 нг/мл, диагностическая чувствительность выявления первичного рака почки составила 84%, специфичность по отношению к «здоровому» контролю – 87,5%, к «патологическому» контролю (здоровые доноры + больные доброкачественными опухолями почки) – 73%. Наилучшее соотношение чувствительности и специфичности для ТИМП-1 составило 67 и 65% при пороговом уровне 315 нг/мл. Для ММП-8 не удалось найти порогового уровня с приемлемым соотношением чувствительности и специфичности. Уровни всех трех маркеров положительно коррелировали со стадией заболевания и показателями системы TNM, а уровни ММП-7 и ТИМП-1 возрастали по мере уменьшения степени дифференцировки опухоли. У 5 пациентов, обследованных на фоне прогрессирования, уровни всех маркеров были существенно выше, чем у первичных больных, и превышали рассчитанные пороговые значения. Заключение. Наиболее перспективным серологическим маркером рака почки следует считать ММП-7: ее содержание в сыворотке крови уже на I стадии заболевания превышает пороговый уровень в 84% случаев. ТИМП-1 обладает приемлемой чувствительностью (70% и более) только начиная со II стадии рака почки. Уровень ММП-8 увеличивается лишь при III–IV стадиях заболевания.
Список литературы
1. Ainsworth NL, Lee JS, Eisen T. Impact of anti-angiogenic treatments on metastatic renal cell carcinoma. Expert Rev Anticancer Ther. 2009;9(12):1793–805. doi:10.1586/era.09.144.
2. Srinivasan R, Armstrong AJ, Dahut W, George DJ. Anti-angiogenic therapy in renal cell cancer. BJU Int. 2007;99(5 Pt B):1296–300. doi:10.1111/j.1464-410X.2007.06834.x.
3. Oya M. Renal cell carcinoma: biological features and rationale for molecular-targeted therapy. Keio J Med. 2009;58(1):1–11. doi: http://doi.org/10.2302/kjm.58.1.
4. Virman JP, Bono P, Luukkaala TH, Sunela KL, Kujala PM, Kellokumpu-Lehtinen PL. Combined Angiogenesis and Proliferation Markers' Expressions as Long-Term Prognostic Factors in Renal Cell Cancer. Clin Genitourin Cancer. 2016;14(4):e283–9. doi:10.1016/j.clgc.2015.12.014.
5. Герштейн ЕС, Кушлинский НЕ. Клинические перспективы исследования ассоциированных с опухолью протеаз и их тканевых ингибиторов у онкологических больных. Вестник Российской академии медицинских наук. 2013;68(5):16–27.
6. Deryugina EI, Quigley JP. Pleiotropic roles of matrix metalloproteinases in tumor angiogenesis: contrasting, overlapping and compensatory functions. Biochim Biophys Acta. 2010;1803(1):103–20. doi:10.1016/j.bbamcr.2009.09.017.
7. Abdel-Wahed MM, Asaad NY, Aleskandarany M. Expression of matrix metalloproteinase-2 in renal cell carcinoma. J Egypt Natl Canc Inst. 2004;16(3):168–77.
8. Cheng HP, Duan YR, Li Y, Li XD, Zhu CY, Chen BP. Clinicopathological significance of matrix metalloproteinase-2 protein expression in renal cell carcinoma patients. Anal Quant Cytopathol Histpathol. 2015;37(6):353–63.
9. Cho NH, Shim HS, Rha SY, Kang SH, Hong SH, Choi YD, Hong SJ, Cho SH. Increased expression of matrix metalloproteinase 9 correlates with poor prognostic variables in renal cell carcinoma. Eur Urol. 2003;44(5):560–6. doi: http://doi.org/10.1016/S0302-2838(03)00362-2.
10. Lu H, Yang Z, Zhang H, Gan M, Zhou T, Wang S. The expression and clinical significance of matrix metalloproteinase 7 and tissue inhibitor of matrix metalloproteinases 2 in clear cell renal cell carcinoma. Exp Ther Med. 2013;5(3):890–6. doi: 10.3892/etm.2012.859.
11. Qiao ZK, Li YL, Lu HT, Wang KL, Xu WH. Expression of tissue levels of matrix metalloproteinases and tissue inhibitors of metalloproteinases in renal cell carcinoma. World J Surg Oncol. 2013;11:1. doi:10.1186/1477-7819-11-1.
12. DI Carlo A. Matrix metalloproteinase-2 and -9 and tissue inhibitor of metalloproteinase-1 and -2 in sera and urine of patients with renal carcinoma. Oncol Lett. 2014;7(3):621–6. doi:10.3892/ol.2013.1755.
13. Lein M, Jung K, Laube C, Hübner T, Winkelmann B, Stephan C, Hauptmann S, Rudolph B, Schnorr D, Loening SA. Matrix-metalloproteinases and their inhibitors in plasma and tumor tissue of patients with renal cell carcinoma. Int J Cancer. 2000;85(6):801–4. doi:10.1002/(SICI)1097-0215(20000315)85:63.0.CO;2-C.
14. Ramankulov A, Lein M, Johannsen M, Schrader M, Miller K, Jung K. Plasma matrix metalloproteinase-7 as a metastatic marker and survival predictor in patients with renal cell carcinomas. Cancer Sci. 2008;99(6):1188–94. doi:10.1111/j.1349-7006.2008.00802.x.
15. Niedworok C, vom Dorp F, Tschirdewahn S, Rübben H, Reis H, Szucs M, Szarvas T. Validation of the diagnostic and prognostic relevance of serum MMP-7 levels in renal cell cancer by using a novel automated fluorescent immunoassay method. Int Urol Nephrol. 2016;48(3): 355–61. doi:10.1007/s11255-015-1185-8.
16. Ban CR, Twigg SM, Franjic B, Brooks BA, Celermajer D, Yue DK, McLennan SV. Serum MMP-7 is increased in diabetic renal disease and diabetic diastolic dysfunction. Diabetes Res Clin Pract. 2010;87(3):335–41. doi:10.1016/j.diabres.2010.01.004.
17. Basu RK, Donaworth E, Siroky B, Devarajan P, Wong HR. Loss of matrix metalloproteinase-8 is associated with worsened recovery after ischemic kidney injury. Ren Fail. 2015;37(3): 469–75. doi:10.3109/0886022X.2014.996842.
18. Chang HR, Yang SF, Li ML, Lin CC, Hsieh YS, Lian JD. Relationships between circulating matrix metalloproteinase-2 and -9 and renal function in patients with chronic kidney disease. Clin Chim Acta. 2006;366(1–2):243–8. doi:10.1016/j.cca.2005.10.007.
19. Hsiao KC, Tsai JP, Yang SF, Lee WC, Huang JY, Chang SC, Hso CS, Chang HR. MMP-2 serum concentrations predict mortality in hemodialysis patients: a 5-year cohort study. Clin Chim Acta. 2016;452:161–6. doi:10.1016/j.cca.2015.11.019.
20. Lu LC, Yang CW, Hsieh WY, Chuang WH, Lin YC, Lin CS. Decreases in plasma MMP-2/TIMP-2 and MMP-9/TIMP-1 ratios in uremic patients during hemodialysis. Clin Exp Nephrol. 2016;20(6): 934–42. doi:10.1007/s10157-015-1221-0.
Almanac of Clinical Medicine. 2017; 45: 94-101
Matrix metalloproteinases 2, 7, 8, 9 and their type 1 tissue inhibitor in serum of renal cancer patients: clinical and pathologic correlations
https://doi.org/10.18786/2072-0505-2017-45-2-94-101Abstract
Background: The cause of late diagnosis of renal cancer lies in its durable, almost asymptomatic course. Due to the use of antiangiogenic therapies much progress has been made in its treatment in recent years. Yet, many questions concerning the diagnosis, prognosis and prediction of the efficiency of targeted therapy remain unsolved. Therefore, exploration of new renal cancer molecular markers, especially those related to its angiogenic and invasive activities, are still on the agenda. Such markers include the family of matrix metalloproteinases (MMPs) that degrade the majority of extracellular matrix components and are involved at all stages of tumor progression. Aim: Comparative evaluation of MMP2, 7, 8, 9 and type 1 tissue inhibitor (TIMP-1) levels in serum of healthy individuals and patients with renal cancer or benign renal tumors, analysis of their associations with the main clinical and pathologic characteristics of the disease. Materials and methods: We examined 99 renal cancer patients (of those 94 with primary tumor and 5 at progression) and 10 patients with benign renal tumors. The control group included 97 healthy individuals. Levels of the proteins studied were measured using respective direct ELISA kits (Quantikine®, R&D Systems, USA). Results: MMP-7, MMP-8 and TIMP-1 levels in the sera of renal cancer patients were significantly higher than in the control group and in benign renal tumor patients. MMP-2 and MMP-9 levels did not differ significantly between the study and control groups. At MMP-7 cut-off level of 3.0 ng/mL, its diagnostic sensitivity for primary renal cancer was 84%, specificity in relation to “healthy” control – 87.5%, in relation to the pathologic control (healthy donors+benign renal tumor patients) – 73%. The best sensitivity: specificity ratio for TIMP-1 was 67 and 65% at the cut-off level of 315 ng/ml. No cut-off value with acceptable sensitivity: specificity ratio was found for MMP-8. Serum levels of all these 3 markers were positively associated with disease stage and TNM indices; MMP-7 and TIMP-1 levels also increased with lower differentiation grade. In 5 patients evaluated at disease progression the levels of all the markers studied were markedly higher than in the primary patients, and exceeded the estimated cut-off values. Conclusion: MMP-7 should be regarded as the most promising serological renal cancer marker; its serum levels exceed the cut-off value even in 84% stage I patients. TIMP-1 has acceptable sensitivity (70% and above) only from stage II renal cancer onwards, while MMP-8 levels are increased only at stage III–IV of the disease.
References
1. Ainsworth NL, Lee JS, Eisen T. Impact of anti-angiogenic treatments on metastatic renal cell carcinoma. Expert Rev Anticancer Ther. 2009;9(12):1793–805. doi:10.1586/era.09.144.
2. Srinivasan R, Armstrong AJ, Dahut W, George DJ. Anti-angiogenic therapy in renal cell cancer. BJU Int. 2007;99(5 Pt B):1296–300. doi:10.1111/j.1464-410X.2007.06834.x.
3. Oya M. Renal cell carcinoma: biological features and rationale for molecular-targeted therapy. Keio J Med. 2009;58(1):1–11. doi: http://doi.org/10.2302/kjm.58.1.
4. Virman JP, Bono P, Luukkaala TH, Sunela KL, Kujala PM, Kellokumpu-Lehtinen PL. Combined Angiogenesis and Proliferation Markers' Expressions as Long-Term Prognostic Factors in Renal Cell Cancer. Clin Genitourin Cancer. 2016;14(4):e283–9. doi:10.1016/j.clgc.2015.12.014.
5. Gershtein ES, Kushlinskii NE. Klinicheskie perspektivy issledovaniya assotsiirovannykh s opukhol'yu proteaz i ikh tkanevykh ingibitorov u onkologicheskikh bol'nykh. Vestnik Rossiiskoi akademii meditsinskikh nauk. 2013;68(5):16–27.
6. Deryugina EI, Quigley JP. Pleiotropic roles of matrix metalloproteinases in tumor angiogenesis: contrasting, overlapping and compensatory functions. Biochim Biophys Acta. 2010;1803(1):103–20. doi:10.1016/j.bbamcr.2009.09.017.
7. Abdel-Wahed MM, Asaad NY, Aleskandarany M. Expression of matrix metalloproteinase-2 in renal cell carcinoma. J Egypt Natl Canc Inst. 2004;16(3):168–77.
8. Cheng HP, Duan YR, Li Y, Li XD, Zhu CY, Chen BP. Clinicopathological significance of matrix metalloproteinase-2 protein expression in renal cell carcinoma patients. Anal Quant Cytopathol Histpathol. 2015;37(6):353–63.
9. Cho NH, Shim HS, Rha SY, Kang SH, Hong SH, Choi YD, Hong SJ, Cho SH. Increased expression of matrix metalloproteinase 9 correlates with poor prognostic variables in renal cell carcinoma. Eur Urol. 2003;44(5):560–6. doi: http://doi.org/10.1016/S0302-2838(03)00362-2.
10. Lu H, Yang Z, Zhang H, Gan M, Zhou T, Wang S. The expression and clinical significance of matrix metalloproteinase 7 and tissue inhibitor of matrix metalloproteinases 2 in clear cell renal cell carcinoma. Exp Ther Med. 2013;5(3):890–6. doi: 10.3892/etm.2012.859.
11. Qiao ZK, Li YL, Lu HT, Wang KL, Xu WH. Expression of tissue levels of matrix metalloproteinases and tissue inhibitors of metalloproteinases in renal cell carcinoma. World J Surg Oncol. 2013;11:1. doi:10.1186/1477-7819-11-1.
12. DI Carlo A. Matrix metalloproteinase-2 and -9 and tissue inhibitor of metalloproteinase-1 and -2 in sera and urine of patients with renal carcinoma. Oncol Lett. 2014;7(3):621–6. doi:10.3892/ol.2013.1755.
13. Lein M, Jung K, Laube C, Hübner T, Winkelmann B, Stephan C, Hauptmann S, Rudolph B, Schnorr D, Loening SA. Matrix-metalloproteinases and their inhibitors in plasma and tumor tissue of patients with renal cell carcinoma. Int J Cancer. 2000;85(6):801–4. doi:10.1002/(SICI)1097-0215(20000315)85:63.0.CO;2-C.
14. Ramankulov A, Lein M, Johannsen M, Schrader M, Miller K, Jung K. Plasma matrix metalloproteinase-7 as a metastatic marker and survival predictor in patients with renal cell carcinomas. Cancer Sci. 2008;99(6):1188–94. doi:10.1111/j.1349-7006.2008.00802.x.
15. Niedworok C, vom Dorp F, Tschirdewahn S, Rübben H, Reis H, Szucs M, Szarvas T. Validation of the diagnostic and prognostic relevance of serum MMP-7 levels in renal cell cancer by using a novel automated fluorescent immunoassay method. Int Urol Nephrol. 2016;48(3): 355–61. doi:10.1007/s11255-015-1185-8.
16. Ban CR, Twigg SM, Franjic B, Brooks BA, Celermajer D, Yue DK, McLennan SV. Serum MMP-7 is increased in diabetic renal disease and diabetic diastolic dysfunction. Diabetes Res Clin Pract. 2010;87(3):335–41. doi:10.1016/j.diabres.2010.01.004.
17. Basu RK, Donaworth E, Siroky B, Devarajan P, Wong HR. Loss of matrix metalloproteinase-8 is associated with worsened recovery after ischemic kidney injury. Ren Fail. 2015;37(3): 469–75. doi:10.3109/0886022X.2014.996842.
18. Chang HR, Yang SF, Li ML, Lin CC, Hsieh YS, Lian JD. Relationships between circulating matrix metalloproteinase-2 and -9 and renal function in patients with chronic kidney disease. Clin Chim Acta. 2006;366(1–2):243–8. doi:10.1016/j.cca.2005.10.007.
19. Hsiao KC, Tsai JP, Yang SF, Lee WC, Huang JY, Chang SC, Hso CS, Chang HR. MMP-2 serum concentrations predict mortality in hemodialysis patients: a 5-year cohort study. Clin Chim Acta. 2016;452:161–6. doi:10.1016/j.cca.2015.11.019.
20. Lu LC, Yang CW, Hsieh WY, Chuang WH, Lin YC, Lin CS. Decreases in plasma MMP-2/TIMP-2 and MMP-9/TIMP-1 ratios in uremic patients during hemodialysis. Clin Exp Nephrol. 2016;20(6): 934–42. doi:10.1007/s10157-015-1221-0.
