Инсулиноподобные факторы роста у больных с опухолями яичника (результаты собственного исследования)

Князев Р.И., Кузнецов В.В., Бокин И.И. и др. Инсулиноподобные факторы роста у больных с опухолями яичника (результаты собственного исследования). Современная Онкология. 2016; 18 (1): 67–74.

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Knyazev R.I., Kuznetsov V.V., Bokin I.I. et al. Insulin-like growth factors in patients with ovarian tumors (results of own research). Journal of Modern Oncology. 2016; 18 (1): 67–74.

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Аннотация

В экспериментальных моделях показано, что семейство инсулиноподобных факторов роста (ИФР), основным представителем которого является ИФР 1-го типа, проявляет митогенную, антиапоптотическую и ангиогенную активность. Известно, что ИФР-сигнальный путь участвует в активации каскада митогенактивируемых протеинкиназ, приводящих к блокированию апоптоза. Клинические работы подтверждают необходимость участия ИФР-сигнального пути в развитии и прогрессировании рака яичника (РЯ).
Материалы и методы. В исследование включены 44 больных РЯ, 7 пациенток с пограничными и 14 – доброкачественными опухолями яичника. Иммуноферментным анализом определено содержание ИФР 1 и 2-го типа в опухолевой ткани и сыворотке крови у больных с новообразованиями яичника.
Результаты. В ткани РЯ содержание ИФР-1 достоверно ниже, чем в ткани доброкачественных опухолей. Сывороточные уровни ИФР-1 и ИФР-2 отрицательно коррелируют с распространенностью РЯ. Обнаружена прямая корреляционная зависимость между уровнями ИФР-1 и ИФР-2 в ткани РЯ, а также слабая достоверная прямая зависимость между сывороточными уровнями ИФР-1 и ИФР-2. Медиана срока наблюдения составила 14 мес, а медиана срока жизни без рецидива – 13,5 мес. Установлено снижение 2-летней безрецидивной выживаемости на 40% при низких уровнях ИФР-1 сыворотки крови и на 30% – при низких значениях ИФР-2. У больных с размером остаточной опухоли менее 1 см при высоких сывороточных уровнях ИФР-1 (более 87 нг/мл) 2-летняя безрецидивная выживаемость составила 66,2%, а при низких уровнях ИФР-1 – 25% (р=0,016).
Выводы. Уровни ИФР-1 и ИФР-2 в опухолевой ткани и сыворотке крови у больных РЯ уменьшались при распространенности опухолевого процесса. Повышенные уровни ИФР-1 могут рассматриваться в качестве фактора благоприятного прогноза у больных РЯ, которым была выполнена циторедуктивная операция с остаточной опухолью менее 1 см.

Ключевые слова: рак яичника, канцерогенез, метастазирование, апоптоз, инсулиноподобные факторы роста, диагностика, прогноз, выживаемость, циторедуктивная операция, опухолевые маркеры.

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In experimental models it was shown that the family of insulin-like growth factors (IGF), the main representative of which is IGF-1 exerts mitogenic, antiapoptotic and angiogenic activity. It is known that IGF-signaling pathway is involved in the activation cascade of the mitogen-activated protein kinases, resulting in the blocking of apoptosis. Clinical studies confirm the need for the involvement of IGF signaling pathway in the development and progression of ovarian cancer (OC).
Subjects and methods. The study included 44 patients with ovarian cancer, 7 patients with borderline and 14 benign ovarian tumors. The ELISA analysis determined the content of insulin-like growth factors type 1 and 2 in tumor tissue and serum of patients with neoplasm of the ovary.
Results. In the tissue of ovarian cancer content of IGF-1 were significantly lower than in the tissue of benign tumors. Serum levels of IGF-1 and IGF-2 correlated negatively with the prevalence of OC. Found direct correlation between levels of IGF-1 and IGF-2 in ovarian cancer tissue, and poor direct correlation between serum levels of IGF-1 and IGF-2. The median follow-up period was 14 months and the median time without recurrence was 13.5 months. It is established that two-year disease-free survival is reduced by 40% when low serum levels of IGF-I, and 30% at low levels of IGF-2. In patients with residual tumor size less than 1 cm with high serum levels of IGF-1 (87 ng/ml) two-year disease-free survival was 66.2%, and at low levels of IGF-1 – 25% (p=0.016).
Conclusions. The levels of IGF-1 and IGF-2 in tumor tissue and serum in patients with ovarian cancer were decreased in the tumor process. Elevated levels of IGF-I can be considered as a factor of favorable prognosis in patients with ovarian cancer who underwent cytoreductive surgery with residual tumor of less than 1 cm.

Key words: ovarian cancer, carcinogenesis, metastasis, apoptosis, insulin-like growth factors, diagnosis, prognosis, survival, cytoreductive surgery, tumor markers.

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Список литературы

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1. King ER, Wong KK. Insulin-like growth factor: current concepts and new developments in cancer therapy. Recent Patents Anti-cancer Drug Dis 2012; 7 (1): 14.
2. Bruchim I, Sarfstein R, Werner H. The IGF hormonal network in endometrial cancer: functions, regulation, and targeting approaches. Front Endocrin 2014; 5.
3. Ma J et al. IGF-1 mediates PTEN suppression and enhances cell invasion and proliferation via activation of the IGF-1/PI3K/Akt signaling pathway in pancreatic cancer cells. J Surg Res 2010; 160 (1): 90–101.
4. Mairet-Coello G, Tury A, DiCicco-Bloom E. Insulin-like growth factor-1 promotes G1/S cell cycle progression through bidirectional regulation of cyclins and cyclin-dependent kinase inhibitors via the phosphatidylinositol 3-kinase/Akt pathway in developing rat cerebral cortex. J Neurosci 2009; 29 (3): 775–88.
5. Rinaldi S et al. Serum levels of IGF‐I, IGFBP‐3 and colorectal cancer risk: results from the EPIC cohort, plus a meta‐analysis of prospective studies. Int J Cancer 2010; 126 (7): 1702–15.
6. Cao Y et al. Prediagnostic plasma IGFBP‐1, IGF‐1 and risk of prostate cancer. Int J Cancer 2015; 136 (10): 2418–26.
7. Hormones TE, Group BCC. Insulin-like growth factor 1 (IGF1), IGF binding protein 3 (IGFBP3), and breast cancer risk: pooled individual data analysis of 17 prospective studies. Lancet Oncol 2010; 11 (6): 530–42.
8. Bochkareva N.V., Kondakova I.V., Kolomiets L.A. i dr. Insulinopodobnye faktory rosta i sviazyvaiushchie ikh belki v patogeneze raka endometriia. Sib. onkol. zhurn. 2008; 3: 27. [in Russian]
9. Flannery CA et al. SAT-0017: Differential Expression of IR-a, IR-B and IGF-1R in Endometrium Reflects Physiology during the Menstrual Cycle and Demonstrates a Distinct Expression Signature in Endometrial Adenocarcinoma. 2014.
10. Digaeva M.A. Prediktory epitelial'nykh opukholei iaichnikov, ikh rol' v patogeneze, diagnostike, taktike vybora ob"ema operativnogo lecheniia i prognoze. Avtoref. dis. … d-ra med. nauk. M., 2011. [in Russian]
11. An Y et al. Local expression of insulin-like growth factor-I, insulin-like growth factor-I receptor, and estrogen receptor alpha in ovarian cancer. Oncol Res Treat 2009; 32 (11): 638–44.
12. Brokaw J et al. IGF-I in epithelial ovarian cancer and its role in disease progression. Growth Factors 2007; 25 (5): 346–54.
13. Lu L et al. The relationship of insulin-like growth factor-II, insulin-like growth factor binding protein-3, and estrogen receptor-alpha expression to disease progression in epithelial ovarian cancer. Clin Cancer Res 2006; 12 (4): 1208–14.
14. Sayer RA et al. 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.
15. Spentzos D et al. IGF axis gene expression patterns are prognostic of survival in epithelial ovarian cancer. Endocrine-related Cancer 2007; 14 (3): 781–90.
16. Ose J et al. Insulin-like growth factor I and risk of epithelial invasive ovarian cancer by tumour characteristics: results from the EPIC cohort. Br J Cancer 2015; 112 (1): 162–6.
17. Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 2008; 8 (12): 915–28.
18. Mikami K et al. Prostate cancer risk in relation to insulin-like growth factor (IGF)-I and IGF-binding protein-3: A nested case-control study in large scale cohort study in Japan. Asian Pac J Cancer Prevention: APJCP 2009; 10: 57–61.
19. Sakauchi F et al. Serum Insulin-like Growth Factors I and II, Insulin-like Growth Factor Binding Protein-3 and Risk of Breast Cancer in the JACC Study. Asian Pac J Cancer Prevent 2009; 10: 51–5.
20. Suzuki S et al. Insulin-like Growth Factor (IGF)-I, IGF-II, IGF Binding Protein-3, and Risk of Colorectal Cancer: a Nested Case-control Study in the JACC Study. Age 2009; 64 (8.1): 64.9–8.3.
21. Tas F et al. Clinical significance of serum insulin-like growth factor-1 (IGF-1) and insulinlike growth factor binding protein-3 (IGFBP-3) in patients with epithelial ovarian cancer. Tumor Biology 2014; 35 (4): 3125–32.
22. Huang YF et al. Circulating IGF system and treatment outcome in epithelial ovarian cancer. Endocrine-related Cancer 2014; 21 (2): 217–29.

Авторы

Р.И.Князев1, В.В.Кузнецов2, И.И.Бокин1, В.В.Баринов2, Н.Е.Кушлинский2, И.В.Поддубная1,2

1 ГБОУ ДПО Российская медицинская академия последипломного образования Минздрава России. 125993, Россия, Москва, ул. Баррикадная, д. 2/1;
2 ФГБУ Российский онкологический научный центр им. Н.Н.Блохина Минздрава России. 115478, Россия, Москва, Каширское ш., д. 23
*sluwba@mail.ru

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R.I.Knyazev1, V.V.Kuznetsov2, I.I.Bokin1, V.V.Barinov2, N.E.Kushlinskiy2, I.V.Poddubnaya1,2

1 Russian Medical Academy of Postgraduate Education of the Ministry of Health of the Russian Federation. 125993, Russian Federation, Moscow, ul. Barrikadnaia, d. 2/1;
2 N.N.Blokhin Russian Cancer Research Center of the Ministry of Health of the Russian Federation. 115478, Russian Federation, Moscow, Kashirskoe sh., d. 23
*sluwba@mail.ru

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