Annals of the Russian academy of medical sciencesAnnals of the Russian academy of medical sciencesВестник Российской академии медицинских наук0869-60472414-3545"Paediatrician" Publishers LLC34210.15690/vramn.v67i2.119ONCOLOGY: CURRENT ISSUESАКТУАЛЬНЫЕ ВОПРОСЫ ОНКОЛОГИИVEGF IN NEOPLASTIC ANGIOGENESISРОЛЬ VEGF В РАЗВИТИИ НЕОПЛАСТИЧЕСКОГО АНГИОГЕНЕЗАChekhoninV. P.ЧехонинВ. П.
Russian Federation

доктор медицинских наук, профессор, академик РАМН, заведующий Отделом фундаментальной и прикладной нейробиологии ФГУССП, заведующий кафедрой медицинских нанобиотехно- логий РГМУ Адрес: 119034, Москва, пер. Кропоткинский, д. 23 Тел.: (495) 695-02-62, факс: (495) 636-50-55

chekhoninnew@yandex.ruSheinS. A.ШеинС. А.
Russian Federation

аспирант кафедры медицинских нанобиотехнологий Адрес: 119634, Москва, ул. Лукинская, д. 11, кв. 191 Тел.: (916) 108-35-09

atomos@rambler.ruKorchaginaA. A.КорчагинаА. А.
Russian Federation

аспирант кафедры медицинских нанобиотехнологий Адрес: 121601, Москва, Филевский бульвар, д. 11, кв. 84 Тел.: (910) 433-17-76

avilis1@yandex.ruGurinaO. I.ГуринаО. И.
Russian Federation

доктор медицинских наук, руководитель лаборатории нейрохимии ФГУССП Адрес: 117587, Москва, Варшавское шоссе, д. 114/1, кв. 364 Тел.: (495) 695-02-62

olga672@yandex.ruFSI «Serbsky State scientific centre of social and forensic psychiatry» Ministry of Healthcare and Social development, Moscow Pirogov Russian National scientific medical university, Ministry of Healthcare and Social Development of Russia, MoscowФГУ «Государственный научный центр социальной и судебной психиатрии им. В.П. Сербского» Минздравсоцразвития России, Москва ГБОУ ВПО «Российский национальный исследовательский медицинский университет имени Н.И. Пирогова» Минздравсоцразвития России, МоскваPirogov Russian National scientific medical university, Ministry of Healthcare and Social Development of Russia, MoscowГБОУ ВПО «Российский национальный исследовательский медицинский университет имени Н.И. Пирогова» Минздравсоцразвития России, МоскваFSI «Serbsky State scientific centre of social and forensic psychiatry» Ministry of Healthcare and Social development, MoscowФГУ «Государственный научный центр социальной и судебной психиатрии им. В.П. Сербского» Минздравсоцразвития России, Москва22022012672Vestnik Rossiiskoi akademii medetsinskikh nauk / Annals of the Russian academy of medical sciencesВестник Российской академии медицинских наук233407082015Copyright ©; 2012, "Paediatrician" Publishers LLCCopyright ©; 2012, Издательство "Педиатръ"2012"Paediatrician" Publishers LLCИздательство "Педиатръ"https://vestnikramn.spr-journal.ru/jour/article/view/342

Solid tumor progression largely depends on vascularization and angiogenesis in the malignant tissue. The most prominent among all proangiogenic factors is vascular endothelium growth factor (VEGF). VEGF suppression leads to retrogression of neoplastic vessels and tumor growth restriction. Clinical trials of complex antiangiogenic and chemical therapy of different neoplastic tumors have shown promising results. Nowadays bevacizumab is widely used in breast cancer, colorectal cancer and II-IV stage of malignancy gliomas treatment. Unfortunately, in the majority of cases antiangiogenic treatment led not to full recovery, but only to tumor development restriction. Resistance mechanisms include potentiating of alternative proangiogenic signaling pathways and activation of malignant cell invasive population.

Прогрессия солидных опухолей во многом зависит от степени васкуляризации и ангиогенеза малигнизированной ткани. Из целого спектра проангиогенных факторов наиболее серьезное значение имеет фактор роста эндотелия сосудов (VEGF). Подавление функций VEGF приводит к регрессии неопластических сосудов и ограничению роста опухоли. Многообещающие результаты продемонстрировали клинические испытания комплексной антиангиогенной и химиотерапии различных неопластических образований. В настоящее время препарат бевацизумаб вошел в широкую клиническую практику при терапии рака молочной железы, колоректального рака и глиом III–IV степени злокачественности. К сожалению, в большинстве случаев антиангиогенная терапия не приводит к полному выздоровлению, а лишь замедляет развитие опухоли. Механизмы резистентности включают потенцирование альтернативных проангиогенных сигнальных путей и активацию инвазивной популяции опухолевых клеток.

bevacizumabangiogenesisVEGFantiangiogenic treatmentgliomaбевацизумабангиогенезVEGFантиангиогенная терапияглиома1. Folkman J. Angiogenesis. Ann. Rev. Med. 2006; 57: 1–18.2. Ferrara N., Gerber H.P., LeCouter J. The biology of VEGF and its receptors. Nature Med. 2003; 9 (6): 669−676.3. Ferrara N. VEGF and the quest for tumour angiogenesis factors. Nature Rev. Cancer. 2002; 2 (10): 795−803.4. Guiu S. et al. Bevacizumab/irinotecan. An active treatment for recurrent high grade gliomas: preliminary re-sults of an ANOCEF Multicenter Study. Rev. Neurol. 2008; 164 (6−7): 588–594.5. Norden A.D. et al. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recur-rence. Neurology. 2008; 70 (10): 779–787.6. Pope W.B., Lai A., Nghiemphu P. et al. MRI in patients with high-grade gliomas treated with bevacizumab and chemotherapy. Neurology. 2006; 67 (11): 1258–1260.7. Norden A.D., Drappatz J., Wen P.Y. Antiangiogenic therapies for high-grade glioma. Nature Rev. Neurol. 2009; 5 (11): 610–620.8. Narayana A. et al. Antiangiogenic therapy using bevacizumab in recurrent high-grade glioma: impact on local control and patient survival. J. Neurosurg. 2009; 110 (1): 173–180.9. Nghiemphu P.L. et al. Bevacizumab and chemotherapy for recurrent glioblastoma: a single-institution experi-ence. Neurology. 2009; 72 (14): 1217–1222.10. Poulsen H.S. et al. Bevacizumab plus irinotecan in the treatment patients with progressive recurrent malig-nant brain tumours. Acta Oncol. 2009; 48 (1): 52–58.11. Zuniga R.M. et al. Efficacy, safety and patterns of response and recurrence in patients with recurrent high-grade gliomas treated with bevacizumab plus irinotecan. J. Neurooncol. 2009; 91 (3): 329–336.12. Stupp R. et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009; 10 (5): 459–466.13. Vredenburgh J.J. et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J. Clin. Oncol. 2007; 25 (30): 4722–4729.14. Batchelor T.T. et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell. 2007; 11 (1): 83–95.15. Ferrara N., Carver-Moore K., Chen H. et al. Heterozygous embryonic lethality induced by targeted inactiva-tion of the VEGF gene. Nature. 1996; 380 (6573): 439–442.16. Ferrara N. Vascular Endothelial Growth Factor as a target for anticancer therapy. Oncologist. 2004; 9: 2–10.17. Risau W. Mechanisms of angiogenesis. Nature. 1997; 386 (6626): 671–674.18. Hanai J., Dhanabal M., Karumanchi S.A. et al. Endostatin causes G1 arrest of endothelial cells through inhi-bition of cyclin D1. J Biol Chem. 2002; 277 (19): 16464–16469.19. Rosen L.S. Clinical experience with angiogenesis signaling inhibitors: focus on vascular endothelial growth factor (VEGF) blockers. Cancer Control. 2002; 9: 36–44.20. Robinson C.J., Stringer S.E. The splicevariants of vascular endothelial growth factor (VEGF) and their recep-tors. J Cell Sci. 2001; 114 (5): 853–865.21. Miletic H. et al. Anti-VEGF therapies for malignant glioma: treatment effects and escape mechanisms. Expert Opin. 2009; 13 (4): 455–468.22. Holmes K. et al. Vascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic inhibition. Cell Signal. 2007; 19 (10): 2003–2012.23. Ferrara N., Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. 1997; 18 (1): 4–25.24. Greenberg D.A., Jin K. From angiogenesis to neuropathology. Nature. 2005; 438 (7070): 954–959.25. Shibuya M. Vascular endothelial growth factor receptor-1 (VEGFR1/Flt-1): a dual regulator for angiogenesis. Angiogenesis. 2006; 9 (4): 225–230.26. Brown L.F., Detmar M., Claffey K. et al. Vascular permeability factor/vascular endothelial growth factor: a multifunctional angiogenic. Сytokine Exs. 1997; 79: 233–269.27. Dvorak H.F., Brown L.F., Detmar M. et al. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, andangiogenesis. Am. J. Pathol. 1995; 146 (5): 1029–1039.28. Ferrara N. Molecular and biological properties of vascular endothelial growthfactor. J. Mol. Med. 1999; 77 (7): 527–543.29. Gerber H.P., Dixit V., Ferrara N. Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells. J. Biol. Chem. 1998; 273 (21): 13313–13316.30. Gerber H.P., McMurtrey A., Kowalski J. et al. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J. Biol. Chem. 1998; 273 (46): 30336–30343.31. Testa J.R., Bellacosa A. AKT plays a central role in tumorigenesis. Proc. Natl. Acad. Sci. 2001; 98 (20): 10983–10985.32. Lefranc F., Brotchi J., Kiss R. Possible future issues in the treatment of glioblastomas: special emphasis on cell migration and the resistance of migrating glioblastoma cells to apoptosis. J. Clin. Oncol. 2005; 23 (10): 2411–2422.33. Soung Y.H., Lee J.W., Nam S.W. et al. Mutational analysis of AKT1, AKT2 and AKT3 genes in common human carcinomas. Oncology. 2006; 70 (4): 285–289.34. Lamalice L., Houle F., Huot J. Phosphorylation of Tyr1214 within VEGFR-2 triggers the recruitment of Nck and activation of Fyn leading to SAPK2/p38 activation and endothelial cell migration in response to VEGF. J. Biol. Chem. 2006; 281 (45): 34009–34020.35. Meadows K.N., Bryant P., Pumiglia K. Vascular endothelial growth factor induction of the angiogenic phe-notype requires Ras activation. J. Biol. Chem. 2001; 276 (52): 49289–49298.36. Takahashi T., Yamaguchi S., Chida K. et al. A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent activation of PLC-gamma and DNA synthesis in vascular endothelial cells. EMBO J. 2001; 20 (11): 2768–2778.37. Shibuya M. Structure and function of VEGF/VEGF-receptor system involved in angiogenesis. Cell Struct. Funct. 2001; 26 (1): 25–35.38. Rak J., Yu J.L., Klement G. et al. Oncogenes and angiogenesis: signaling three-dimensional tumor growth. J. Invest. Dermatol. Symp. Proc. 2000; 5 (1): 24–33.39. Plate K.H., Breier G., Weich H.A. et al. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature. 1992; 359 (6398): 845–848.40. Shweiki D., Itin A., Neufeld G. et al. Patterns of expression of vascular endothelial growth factor (VEGF) and VEGF receptors in mice suggest a role in hormonally regulated angiogenesis. J. Clin. Invest. 1993; 91 (5): 2235–2243.41. Weidner N., Semple J.P., Welch W.R. et al. Tumor angiogenesis and metastasis—correlation in invasive breast carcinoma. N. Engl. J. Med. 1991; 324 (1): 1–8.42. Du R. et al. HIF1α induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tu-mor angiogenesis and invasion. Cancer Cell. 2008; 13 (3): 206–220.43. Schmidt N.O., Westphal M., Hagel C. et al. Levels of vascular endothelial growth factor, hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and their relation to angiogenesis. Int. J. Cancer. 1999; 84 (1): 10–18.44. Lee T.H., Avraham H.K., Jiang S. et al. Vascular endothelial growth factor modulates the transendothelial migration of MDA-MB-231 breast cancer cells through regulation of brain microvascular endothelial cell permeability. J. Biol. Chem. 2003; 278 (7): 5277–5284.45. Jain R.K. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination ther-apy. Nature Med. 2001; 7 (9): 987–989.46. Jain R.K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005; 307 (5706): 58–62.47. Holash J. et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Sci-ence. 1999; 284 (5422): 1994–1998.48. Poon R.T., Fan S.T., Wong J. Clinical implications of circulating angiogenic factors in cancer patients. J. Clin. Oncol. 2001; 19 (4): 1207–1225.49. Millauer B., Shawver L.K., Plate K.H. et al. Glioblastoma growth inhibited in vivo by a dominant-negative Flk-1 mutant. Nature. 1994; 367 (6463): 576–579.50. Abramsson A., Berlin O., Papayan H. et al. Analysis of mural cell recruitment to tumor vessels. Circulation. 2002; 105 (1): 112–117.51. Benjamin L.E., Keshet E. Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal. Proc. Natl. Acad. Sci. USA. 1997; 94 (16): 8761–8766.52. Harmey J.H., Bouchier-Hayes D. Vascular endothelial growth factor (VEGF), a survival factor for tumour cells: implications for anti-angiogenic therapy. Bioessays. 2002; 24 (3): 280–283.53. Tran J., Master Z., Yu J.L. et al. A role for survivin in chemoresistance of endothelial cells mediated by VEGF. Proc. Natl. Acad. Sci. USA. 2002; 99 (7): 4349–4354.54. Toi M., Matsumoto T., Bando H. Vascular endothelial growth factor: its prognostic, predictive, and therapeu-tic implications. Lancet Oncol. 2001; 2 (11): 667–673.55. Pegram M.D., Reese D.M. Combined biological therapy of breast cancer using monoclonal antibodies di-rected against HER2/neu protein and vascular endothelial growth factor. Semin. Oncol. 2002; 29: 29–37.56. Nagy J.A., Benjamin L., Zeng H. et al. Vascular permeability, vascular hyperpermeability and angiogenesis. Angiogenesis. 2008; 11 (2): 109–119.57. Bertolini F., Mingrone W., Alietti A. et al. Thalidomide in multiple myeloma, myelodysplastic syndromes and histiocytosis. Analysis of clinical results and of surrogate angiogenesis markers. Ann. Oncol. 2001; 12 (7): 987–990.58. Iruela-Arispe M.L., Luque A., Lee N. Thrombospondin modules and angiogenesis. Int. J. Biochem. Cell Biol. 2004; 36 (6): 1070–1078.59. D'Amato R.J., Loughnan M.S., Flynn E. et al. Thalidomide is an inhibitor of angiogenesis. Proc. Natl. Acad. Sci. USA. 1994; 91 (9): 4082–4085.60. Chaux P., Moutet M., Faivre J. et al. Inflammatory cells infiltrating human colorectal carcinomas express HLA class II but not B7-1 and B7-2 costimulatory molecules of the T-cell activation. Lab. Invest. 1996; 74 (5): 975–983.61. Sallusto F., Cella M., Danieli C. et al. Dendritic cells use macropinocytosis and the mannose receptor to con-centrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products. J. Exp. Med. 1995; 182 (2): 389–400.62. Severin E.S., Rodina A.V. Uspekhi biologicheskoi khimii – Achievements of biological chemistry. 2006; 46: 43–64.63. Menetrier-Caux C., Montmain G., Dieu M.C. et al. Inhibition of the differentiation of dendritic cells from CD 34 (+) progenitors by tumor cells: role of interleukin-6 and macrophage colony-stimulating factor. Blood. 1998; 92 (12): 4778–4791.64. Bergers G., Benjamin L.E. Tumorigenesis and the angiogenic switch. Nature Rev. Cancer. 2003; 3 (6): 401–410.65. Lee C.G., Heijn M., di Tomaso E. et al. Anti-Vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res. 2000; 60 (19): 5565–5570.66. Pham C.D., Roberts T.P., van Bruggen N. et al. Magnetic resonance imaging detects suppression of tumor vascular permeability after administration of antibody to vascular endothelial growth factor. Cancer Invest. 1998; 16 (4): 225–230.67. Brasch R., Pham C., Shames D. et al. Assessing tumor angiogenesis using macromolecular MR imaging con-trast media. J. Magn. Reson. Imag. 1997; 7 (1): 68–74.68. Inai T., Mancuso M., Hashizume H. et al. Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am. J. Pathol. 2004; 165 (1): 35–52.69. Borgstrom P., Gold D.P. et al. Importance of VEGF for breast cancer angiogenesis in vivo: implications from intravital microscopy of combination treatments with an anti-VEGF neutralizing monoclonal antibody and doxorubicin. Anticancer Res. 1999; 19 (5B): 4203–4214.70. Teicher B.A., Holden S.A., Ara G. et al. Potentiation of cytotoxic cancer therapies by TNP-470 alone and with other anti-angiogenic agents. Int. J. Cancer. 1994; 57 (6): 920–925.71. Zhou Q., Guo P., Gallo J.M. Impact of angiogenesis inhibition by sunitinib on tumor distribution of temo-zolomide. Clin. Cancer Res. 2008; 14 (5): 1540–1549.72. Bao S. et al. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth fac-tor. Cancer Res. 2006; 66 (16): 7843–7848.73. Calabrese C. et al. A perivascular niche for brain tumor stem cells. Cancer Cell. 2007; 11 (1): 69–82.74. Marx J. Cancer research. Obstacle for promising cancer therapy. Science. 2002; 295 (5559): 1444.75. Yu J.L., Rak J.W., Coomber B.L. et al. Effect of p53 status on tumor response to antiangiogenic therapy. Sci-ence. 2002; 295 (5559): 1526–1528.76. Wedam S.B., Low J.A., Yang S.X. et al. Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer. J. Clin. Oncol. 2006; 24 (5): 769–777.77. Hurwitz H., Fehrenbacher L., Novotny W. et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for the treatment of metastatic colorectal cancer. N. Engl. J. Med. 2004; 350 (23): 2335–2342.78. Gomez-Manzano C., Holash J., Fueyo J. et al. VEGF Trap induces antiglioma effect at different stages of dis-ease. Neuro Oncol. 2008; 10 (6): 940–945.79. Samoto K., Ikezaki K., Ono M. et al. Expression of vascular endothelial growth factor and its possible rela-tion with neovascularization in human brain tumors. Cancer Res. 1995; 55 (5): 1189–1193.80. Brown L.F., Berse B., Jackman R.W. et al. Expression of vascular permeability factor (vascular endothelial growth factor) and itsreceptors in breast cancer. Hum. Pathol. 1995; 26 (1): 86–91.81. Kunkel P. et al. Inhibition of glioma angiogenesis and growth in vivo by systemic treatment with a mono-clonal antibody against vascular endothelial growth factor receptor-2. Cancer Res. 2001; 61 (18): 6624–6628.82. Lucio-Eterovic A.K., Piao Y., de Groot J.F. Mediators of glioblastoma resistance and invasion during anti-vascular endothelial growth factor therapy. Clin. Cancer Res. 2009; 15 (14): 4589–4599.83. Paez-Ribes M. et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local inva-sion and distant metastasis. Cancer Cell. 2009; 15 (3): 220–231.84. Iwamoto F.M. et al. Patterns of relapse and prognosis after bevacizumab failure in recurrent glioblastoma. Neurology. 2009; 73 (15): 1200–1206.85. Ebos J.M. et al. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogene-sis. Cancer Cell. 2009; 15 (3): 232–239.86. Erber R. et al. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by inter-fering with pericyte-mediated endothelial cell survival mechanisms. FASEB J. 2004; 18 (2): 338–340.87. Zagzag D. et al. Hypoxia-inducible factor 1 and VEGF upregulate CXCR4 in glioblastoma: implications for angiogenesis and glioma cell invasion. Lab. Invest. 2006; 86 (12): 1221–1232.88. Rubin J.B. et al. A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Proc. Natl. Acad. Sci. USA. 2003; 100 (23): 13513–13518.89. Singh S.K., Clarke I.D., Terasaki M. et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003; 63 (18): 5821–5828.90. Singh S.K., Hawkins C., Clarke I.D. et al.Identifi cation of human brain tumour initiating cells. Nature. 2004; 432 (7015): 396–401.91. Galli R., Binda E., Orfanelli U. et al. Isolation and characterization of tumorigenic, stem-like neural precur-sors from human glioblastoma. Cancer Res. 2004; 64 (19): 7011–7021.92. Sakariassen P.O., Prestegarden L., Wang J. et al. Angiogenesis-independent tumor growth mediated by stem-like cancer cells. Proc. Natl. Acad. Sci. USA. 2006; 103 (44): 16466–16471.