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Альманах клинической медицины. 2015; : 19-27

КЛИНИЧЕСКОЕ ЗНАЧЕНИЕ ИССЛЕДОВАНИЯ ИНСУЛИНОПОДОБНЫХ ФАКТОРОВ РОСТА (ИФР) И ИФР-СВЯЗЫВАЮЩИХ БЕЛКОВ У БОЛЬНЫХ НОВООБРАЗОВАНИЯМИ ЯИЧНИКОВ

Герштейн Е. С., Кушлинский Д. Н., Короткова Е. А., Исаева Э. Р., Ермилова В. Д., Лактионов К. П., Адамян Л. В., Кушлинский Н. Е.

https://doi.org/10.18786/2072-0505-2015-41-19-27

Аннотация

Актуальность. Сигнальная система инсулиноподобных факторов роста (ИФР) играет важную роль в возникновении и прогрессии различных злокачественных опухолей, в том числе рака яичников, поэтому ее компоненты рассматриваются в качестве потенциальных диагностических и прогностических маркеров заболевания и мишеней для молекулярно-направленной терапии.
Цель – сравнительная оценка содержания ИФР-I и II и ИФР-связывающих белков (ИФРСБ) 1, 2 и 3 в сыворотке крови и опухолях больных различными новообразованиями яичников, анализ их взаимосвязи с клинико-морфологическими особенностями рака яичников и оценка клинических перспектив определения данных маркеров для диагностики и прогноза заболевания.
Материал и методы. Содержание ИФР-I, II и ИФРСБ-1, 2, 3 определено в сыворотке крови и экстрактах опухолей 74 больных раком, 14 пограничными и 16 доброкачественными опухолями яичников с помощью наборов для прямого иммуноферментного анализа Mediagnost (Германия). В контрольную группу вошли 77 практически здоровых женщин.
Результаты. Выявлено 3 потенциальных серологических маркера рака яичников – ИФРСБ-2, ИФРСБ-1 и ИФР-I. Наилучшее соотношение диагностической чувствительности и специфичности продемонстрировано для ИФРСБ-2: при пороговом уровне 370 нг/мл эти показатели равны 87 и 79% соответственно. Выявленные диагностические маркеры влияют также на прогноз общей выживаемости больных раком яичников, причем низкий уровень ИФР-I имеет независимое неблагоприятное прогностическое значение по данным многофакторного анализа. На прогноз заболевания влияет также содержание ИФР-II и ИФРСБ-1 в ткани опухоли.
Заключение. Выявлены нарушения баланса ИФР/ИФРСБ у больных раком яичников и показано, что отдельные компоненты этой системы могут рассматриваться в качестве диагностических и прогностических маркеров данного заболевания.

Список литературы

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6. An Y, Cai L, Wang Y, Zhu D, Guan Y, Zheng J. Local expression of insulin-like growth factor-I, insulin-like growth factor-I receptor, and estrogen receptor alpha in ovarian cancer. Onkologie. 2009;32(11):638–44. doi: 10.1159/000242253.

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9. Shao M, Hollar S, Chambliss D, Schmitt J, Emerson R, Chelladurai B, Perkins S, Ivan M, Matei D. Targeting the insulin growth factor and the vascular endothelial growth factor pathways in ovarian cancer. Mol Cancer Ther. 2012;11(7):1576–86. doi: 10.1158/1535-7163. MCT-11-0961.

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11. Lu L, Katsaros D, Wiley A, Rigault de la Longrais IA, Puopolo M, Schwartz P, Yu H. Promoter-specific transcription of insulin-like growth factor-II in epithelial ovarian cancer. Gynecol Oncol. 2006;103(3):990–5.

12. Sayer RA, Lancaster JM, Pittman J, Gray J, Whitaker R, Marks JR, Berchuck A. High insulin-like growth factor-2 (IGF-2) gene expression is an independent predictor of poor survival for patients with advanced stage serous epithelial ovarian cancer. Gynecol Oncol. 2005;96(2):355–61.

13. Герштейн ЕС, Исаева ЭР, Кушлинский ДН, Короткова ЕА, Ермилова ВД, Лактионов КП, Адамян ЛВ. Инсулиноподобные факторы роста (ИФР) и ИФР-связывающие белки в сыворотке крови и опухолях больных с новообразованиями яичников. Молекулярная медицина. 2014;(4):52–6.

14. Baron-Hay S, Boyle F, Ferrier A, Scott C. Elevated serum insulin-like growth factor binding protein-2 as a prognostic marker in patients with ovarian cancer. Clin Cancer Res. 2004;10(5):1796–806.

15. Peeters PH, Lukanova A, Allen N, Berrino F, Key T, Dossus L, Rinaldi S, van Gils CH, Bueno-de-Mesquita HB, Boeing H, Schulz M, Chang-Claude J, Linseisen J, Panico S, Sacerdote C, Palli D, Tumino R, Trichopoulou A, Trichopolos D, Bamia C, Larranaga N, Ardanaz E, Pera G, Quirós JR, Martínez-García C, Navarro C, Bingham SA, Khaw KT, Clavel F, Tjonneland A, Olsen A, Overvad K, Tetsche MS, Lund E, Lundin E, Berglund G, Riboli E, Kaaks R. Serum IGF-I, its major binding protein (IGFBP-3) and epithelial ovarian cancer risk: the European Prospective Investigation into Cancer and Nutrition (EPIC). Endocr Relat Cancer. 2007;14(1):81–90.

16. Bruchim I, Werner H. Targeting IGF-1 signaling pathways in gynecologic malignancies. Expert Opin Ther Targets. 2013;17(3):307–20. doi: 10.1517/14728222.2013.749863.

17. Gershtein E, Kushlinskii N. Clinical prospects of IGF-signaling system components study in ovarian cancer patients. Drug Metabol Personal Ther. 2015;30(2):75–85. doi: 10.1515/dmdi2014-0037.

18. Spentzos D, Cannistra SA, Grall F, Levine DA, Pillay K, Libermann TA, Mantzoros CS. IGF axis gene expression patterns are prognostic of survival in epithelial ovarian cancer. Endocr Relat Cancer. 2007;14(3):781–90.

19. Lancaster JM, Sayer RA, Blanchette C, Calingaert B, Konidari I, Gray J, Schildkraut J, Schomberg DW, Marks JR, Berchuck A. High expression of insulin-like growth factor binding protein-2 messenger RNA in epithelial ovarian cancers produces elevated preoperative serum levels. Int J Gynecol Cancer. 2006;16(4):1529–35.

20. Arcidiacono B, Iiritano S, Nocera A, Possidente K, Nevolo MT, Ventura V, Foti D, Chiefari E, Brunetti A. Insulin resistance and cancer risk: an overview of the pathogenetic mechanisms. Exp Diabetes Res. 2012;2012:789174. doi: 10.1155/2012/789174.

21. Bese T, Nomir SK. The importance of serum insulin-like growth factor-I level determination in the follow-up of patients with epi thelial ovarian cancer. Eur J Gynaecol Oncol. 2001;22(5):372–6.

22. Flyvbjerg A, Mogensen O, Mogensen B, Nielsen OS. Elevated serum insulin-like growth factor-binding protein 2 (IGFBP-2) and decreased IGFBP-3 in epithelial ovarian cancer: correlation with cancer antigen 125 and tumor-associated trypsin inhibitor. J Clin Endocrinol Metab. 1997;82(7):2308–13.

23. Shah NG, Bhatavdekar JM, Doctor SS, Suthar TP, Balar DB, Dave RS. Circulating epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I) in patients with epithelial ovarian carcinoma. Neoplasma.1994;41(5):241–3.

24. Tworoger SS, Lee IM, Buring JE, Pollak MN, Hankinson SE. Insulin-like growth factors and ovarian cancer risk: a nested case-control study in three cohorts. Cancer Epidemiol Biomarkers Prev. 2007;16(8):1691–5.

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Almanac of Clinical Medicine. 2015; : 19-27

CLINICAL IMPLICATIONS OF INSULIN-LIKE GROWTH FACTORS (IGF) AND IGF-BINDING PROTEINS INVESTIGATION IN PATIENTS WITH OVARIAN NEOPLASMS

Gershteyn E. S., Kushlinskiy D. N., Korotkova E. A., Isaeva E. R., Ermilova V. D., Laktionov K. P., Adamyan L. V., Kushlinskii N. E.

https://doi.org/10.18786/2072-0505-2015-41-19-27

Abstract

Background: The insulin-like growth factor (IGF) signaling system plays a major role in development and progression of various malignancies including ovarian cancer, and its components are considered as potential diagnostic and prognostic markers and the objects of molecular targeted therapy.
Aim: Comparative evaluation of IGF-I and IGF-II, and IGF-binding proteins (IGFBP)-1, 2 and 3 content in blood serum and tumors of ovarian tumor patients, analysis of their associations with key clinical pathologic characteristics of ovarian cancer and evaluation of clinical value of these markers for disease diagnostics and prognosis.
Materials and methods: IGF-I, II, IGFBP-1, 2 and 3 levels were measured with standard ELISA kits (Mediagnost, Germany) in blood serum and tumor extracts of 74 patients with ovarian cancer, 16 patients with benign and 14 with borderline ovarian tumors. The control group comprised 77 healthy women.
Results: Three potential serological markers of ovarian cancer, namely IGF-I, IGFBP-1, and IGFBP-2 were revealed. The best sensitivity to specificity ratio was demonstrated for IGFBP-2: at a 370 ng/ml cut-off level, these indices were 87 and 79%, respectively. The diagnostic markers found in our study were also associated with the prognosis of overall survival in ovarian cancer. In the multivariate analysis, low IGF-I serum levels retained its independent unfavorable prognostic value. The disease prognosis is influenced also by IGF-II and IGFBP-1 content in the tumor tissue.
Conclusion: In ovarian cancer patients, there is a disbalance of IGFs/IGFBPs. Some components of this system could be potentially used as diagnostic and prognostic markers of the disease.

References

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10. Brokaw J, Katsaros D, Wiley A, Lu L, Su D, Sochirca O, de la Longrais IA, Mayne S, Risch H, Yu H. IGF-I in epithelial ovarian cancer and its role in disease progression. Growth Factors. 2007;25(5):346–54. doi: 10.1080/08977190701838402.

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16. Bruchim I, Werner H. Targeting IGF-1 signaling pathways in gynecologic malignancies. Expert Opin Ther Targets. 2013;17(3):307–20. doi: 10.1517/14728222.2013.749863.

17. Gershtein E, Kushlinskii N. Clinical prospects of IGF-signaling system components study in ovarian cancer patients. Drug Metabol Personal Ther. 2015;30(2):75–85. doi: 10.1515/dmdi2014-0037.

18. Spentzos D, Cannistra SA, Grall F, Levine DA, Pillay K, Libermann TA, Mantzoros CS. IGF axis gene expression patterns are prognostic of survival in epithelial ovarian cancer. Endocr Relat Cancer. 2007;14(3):781–90.

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21. Bese T, Nomir SK. The importance of serum insulin-like growth factor-I level determination in the follow-up of patients with epi thelial ovarian cancer. Eur J Gynaecol Oncol. 2001;22(5):372–6.

22. Flyvbjerg A, Mogensen O, Mogensen B, Nielsen OS. Elevated serum insulin-like growth factor-binding protein 2 (IGFBP-2) and decreased IGFBP-3 in epithelial ovarian cancer: correlation with cancer antigen 125 and tumor-associated trypsin inhibitor. J Clin Endocrinol Metab. 1997;82(7):2308–13.

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