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

Cover Page


Cite item

Full Text

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.

About the authors

E. S. Gershteyn

N.N. Blokhin Russian Cancer Research Center, Moscow

Author for correspondence.
Email: esgershtein@gmail.com
Gershteyn Elena Sergeevna – Doctor of Biol. Sci., Professor, Leading Research Fellow, Clinical Biochemistry Laboratory Russian Federation

D. N. Kushlinskiy

Research Center for Obstetrics, Gynecology and Perinatology named after V.I. Kulakov, Moscow

Email: esgershtein@gmail.com
Kushlinskiy Dmitriy Nikolaevich – Surgeon/ Oncogynecologist, Department of Combined and Complex Methods of Treatment of Gynecological Diseases Russian Federation

E. A. Korotkova

N.N. Blokhin Russian Cancer Research Center, Moscow

Email: esgershtein@gmail.com
Korotkova Ekaterina Andreevna – PhD (Biol.), Senior Research Fellow, Clinical Biochemistry Laboratory Russian Federation

E. R. Isaeva

N.N. Blokhin Russian Cancer Research Center, Moscow

Email: esgershtein@gmail.com
Isaeva Emiliya Rasimovna – Oncologist, Research Polyclinical Department Russian Federation

V. D. Ermilova

N.N. Blokhin Russian Cancer Research Center, Moscow

Email: esgershtein@gmail.com
Ermilova Valeriya Dmitrievna – PhD, Leading Research Fellow, Department of Pathology Russian Federation

K. P. Laktionov

N.N. Blokhin Russian Cancer Research Center, Moscow

Email: esgershtein@gmail.com
Laktionov Konstantin Pavlovich – MD, PhD, Professor, Head of Department of Women’s Reproductive System Tumors Russian Federation

L. V. Adamyan

Research Center for Obstetrics, Gynecology and Perinatology named after V.I. Kulakov, Moscow

Email: esgershtein@gmail.com
Adamyan Leyla Vladimirovna – MD, PhD, Professor, Academician of Russian Academy of Sciences, Deputy Director on Research Russian Federation

N. E. Kushlinskii

N.N. Blokhin Russian Cancer Research Center, Moscow

Email: esgershtein@gmail.com
Kushlinskii Nikolay Evgen’evich – MD, PhD, Professor, Member-Correspondent of Russian Academy of Sciences, Head of Clinical Biochemistry Laboratory Russian Federation

References

  1. Сергеева НС, Маршутина НВ, Алентов ИИ, Корнеева ИА, Новикова ЕГ. Серологические опухолеассоциированные маркеры СА125 и НЕ4 у больных раком яичников. Вопросы онкологии. 2013;59(2):12–21.
  2. Костылева ОИ, Герштейн ЕС, Дигаева МА, Овчинникова ЛК, Бакирханов СК. Инсулиноподобные факторы роста, их рецепторы и связывающие белки как патогенетические факторы и потенциальные мишени терапии в онкологии. Вопросы биологической, медицинской и фармацевтической химии. 2009;7(6):3–8.
  3. Frasca F, Pandini G, Sciacca L, Pezzino V, Squatrito S, Belfiore A, Vigneri R. The role of insulin receptors and IGF-I receptors in cancer and other diseases. Arch Physiol Biochem. 2008;114(1):23–37. doi: 10.1080/13813450801969715.
  4. Butt AJ, Fraley KA, Firth SM, Baxter RC. IGF-binding protein-3-induced growth inhibition and apoptosis do not require cell surface binding and nuclear translocation in human breast cancer cells. Endocrinology. 2002;143(7):2693–9.
  5. Wang GK, Hu L, Fuller GN, Zhang W. An interaction between insulin-like growth factor-bind- ing protein 2 (IGFBP2) and integrin alpha 5 is essential for IGFBP2-induced cell mobility. J Biol Chem. 2006;281(20):14085–91.
  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.
  7. Weroha SJ, Haluska P. The insulin-like growth factor system in cancer. Endocrinol Metab Clin North Am. 2012;41(2):335–50, vi. doi: 10.1016/j.ecl.2012.04.014.
  8. Rho SB, Dong SM, Kang S, Seo SS, Yoo CW, Lee DO, Woo JS, Park SY. Insulin-like growth factor-binding protein-5 (IGFBP-5) acts as a tumor suppressor by inhibiting angiogenesis. Carcinogenesis. 2008;29(11):2106–11. doi: 10.1093/carcin/bgn206.
  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.
  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.
  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.
  25. Масляев АВ, Костылева ОИ, Герштейн ЕС, Ермилова ВД, Грицкевич МВ, Портной СМ. Ин сулиноподобные факторы роста в сыворотке крови больных раком молочной железы. Вопросы биологической, медицинской и фармацевтической химии. 2012;(10):16–20.
  26. Короленкова ЛИ, Кушлинский ДН, Герштейн ЕС, Ермилова ВД, Дворова ЕК. Инсулиноподобные факторы роста сыворотки крови больных цервикальной интраэпителиальной гиперплазией и инвазивным раком шейки матки как перспективные маркеры прогрессии заболевания. Вопросы биологической, медицинской и фармацевтической химии. 2012;(10):21–5.
  27. Кушлинский НЕ, Герштейн ЕС, Николаев АА, Делекторская ВВ, Короткова ЕА, Дворова ЕК, Костылева ОИ. Инсулиноподобные факторы роста (IGF), связывающие IGF белки (IGFBP) и фактор роста эндотелия сосудов (VEGF) в сыворотке крови больных колоректальным раком. Бюллетень экспериментальной биологии и медицины. 2013;156(11):632–6.

Supplementary files

Supplementary Files
Action
1. JATS XML

Copyright (c) 2015 Gershteyn E.S., Kushlinskiy D.N., Korotkova E.A., Isaeva E.R., Ermilova V.D., Laktionov K.P., Adamyan L.V., Kushlinskii N.E.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies