The Effects of VEGF Signal Pathway on Etiopathogenesis and AntiVEGF Treatments in Childhood Cancers

Yıl 2023, , 311 - 317, 24.10.2023

Ali Kazdal Meryem Ertuğrul Selma Söylemez Hikmet Gülşah Tanyıldız

https://doi.org/10.26650/jchild.2023.1173584

Öz

Vascular endothelial growth factor (VEGF) is the most physiologically and pathologically potent angiogenic factor that acts directly on endothelial cells. Its five isoforms, namely, VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF) are present in humans. They bind to three receptors VEGFR-1, VEGFR-2, and VEGFR-3. When they bind to a VEGF receptor, endothelial cell proliferation, migration, apoptosis inhibition, capillary dilatation, and increased capillary permeability occur. VEGFR-1, VEGFR-2, and VEGFR-3 promotes hematopoiesis, angiogenesis, and lymphangiogenesis respectively. Further, VEGFR-1 plays an important role in the migration of endothelial cells; especially in angiogenesis during embryonic development. With VEGFR-2 activation, endothelial cell proliferation and migration occur, and the lifespan of endothelial cells is simultaneously prolonged owing to its antiapoptotic effect. Binding of VEGF-A to VEGFR-2 results in neovascularization of tumor, facilitating tumor metastasis. Thus, VEGF is an essential molecule required for tumor progression and survival. Tumors wherein VEGF plays a role in their pathophysiology generally have a poor prognosis. Such tumors, if untreated can eventually cause the death of patients. Inhibiting VEGF from binding to its receptor is one of the treatment methods: to prevent thşs situation. Therefore, anti-VEGF therapy is important in the treatment protocols of such tumors. The Food and Drug Administration in 2004 approved the first monoclonal antibody, bevacizumab, which binds to and inactivates all isoforms of VEGF-A. Binding to VEGF-A prevents its interaction with VEGFR-1 and VEGFR-2, thereby inhibiting the VEGF signaling pathways that facilitate neovascularization. This inhibition leads to decreased neovascularization of tumor blood vessels and limits blood flow to tumor tissues. Furthermore, it reduces the tissue interstitial pressure and increases blood vessels permeability, thereby increasing the distribution of chemotherapeutic agents and promoting apoptosis of tumor endothelial cells. Bevacizumab is currently used parenterally in combination with chemotherapeutics in many cancer treatments. The dosage of bevacizumab in combined treatments is 10-15 mg/kg intravenously every 2-3 weeks. This review not only investigates the role and importance of VEGF in tumor pathophysiology in childhood cancers but also compiles information regarding new treatment alternatives.

Anahtar Kelimeler

angiogenesis, vascular endothelial growth factor, VEGF, bevacizumab

Çocukluk Çağı Kanserlerinde VEGF Sinyal Yolağının Etiyopatogeneze Etkisi ve Anti-VEGF Tedaviler

Öz

Vasküler endotelyal büyüme faktörü (Vascular Endothelial Growth Factor, VEGF) endotel hücrelerine direkt olarak etkiyen fizyolojik ve patolojik olarak en güçlü anjiyogenik moleküldür. İnsanlarda VEGF ailesi adı altında 5 adet VEGF tipi bulunmaktadır; VEGF-A, VEGF-B, VEGF-C, VEGF-D ve plasental büyüme faktörü (Placental Growth Factor, PlGF). VEGF’nin bağlanabileceği üç reseptör vardır; VEGFR-1 (VEGF reseptörü), VEGFR-2, VEGFR-3. VEGF reseptörüne bağlanınca; endotel hücre proliferasyonu, endotel hücre migrasyonu, apopitozisin inhibisyonu, kapiller dilatasyon ve geçirgenliğin artışı sağlanmış olur. Temel olarak VEGFR-1 hematopoezi, VEGFR-2 anjiyogenezi ve VEGFR-3 de lenfanjiyogenezi destekler. VEGFR-1 endotel hücrelerinin migrasyonunda önemli bir rol oynar. Özellikle de embriyonik gelişimde anjiyogenezde rol oynamaktadır. VEGFR-2’nin aktivasyonuyla; endotel hücre proliferasyonu, migrasyonu gerçekleşir ve aynı zamanda anti-apopitotik etkisiyle endotel hücrelerinin ömrü uzar. VEGF-A’nın VEGFR-2’ye bağlanması sonucu tümör neovaskülarizasyonu sağlanır ve tümörün metastaz yapması kolaylaşır. VEGF tümör progresyonunda ve sağkalımda rol oynayan temel moleküllerden biridir. VEGF’nin patofizyolojisinde rol oynadığı tümörler genellikle kötü prognozludur ve eğer tedavi edilmezlerse maalesef ölüm kaçınılmazdır. Bunu engellemek için tümörün progresyonunda önemli bir molekül olan VEGF’nin reseptörüne bağlanmasını engellemek tedavi yöntemlerinden biri olabilir. Bu yüzden de anti-VEGF tedaviler bu tümörlerin tedavi protokollerinde önemli bir yer tutmaktadır. Bevacizumab, 2004’te Amerika Birleşik Devletleri Gıda ve İlaç Dairesi (Food and Drug Administration, FDA) tarafından onaylanan ilk monoklonal antikordur. Bevacizumab; VEGF-A’nın tüm izoformlarını bağlayan ve inaktive eden bir ajandır, bu bağlanma sonucunda da VEGF-A’nın VEGFR-1 ve VEGFR-2 ile etkileşimini önler ve böylece neovaskülarizasyonu sağlayan VEGF sinyal yollarını inhibe eder. Bu inhibisyon, tümör kan damarlarının neovaskülarizasyonunda azalmaya yol açar ve böylece tümör dokularına kan akışını sınırlar. Bu etkiler ayrıca doku interstisyel basıncını düşürür, kan damarlarının geçirgenliği arttırır ve bu yolla kemoterapötik ajanların dağılımını arttırır ve tümör endotel hücrelerinin apopitozunu destekler. Bevacizumab günümüzde birçok kanser tedavisinde kemoterapötiklerle kombine olarak parenteral yolla kullanılmaktadır. Bevacizumabın kombine tedavilerde kullanımı 2-3 haftada bir intravenöz 10-15mg/kg’dır. Bu derleme; VEGF’in tümör patofizyolojisindeki yerini ve önemini son gelişmeler doğrultusunda irdelemeyi ve yeni tedavi alternatifleri hakkındaki bilgileri sunmayı amaçlamaktadır.

Anahtar Kelimeler

anjiyogenesis, vasküler endoteliyal büyüme faktörü, VEGF, bevacizumab

Kaynakça

• Melincovici CS, Boşca AB, Şuşman S, Mârginean M, Mihu C, Istrate M, et al. Vascular endothelial growth factor (VEGF) - key factor in normal and pathological angiogenesis. Rom J Morphol Embryol 2018;59(2):455-467. google scholar
• Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J of Clin Oncol 005 Feb 10;23(5):1011-27. google scholar
• Ollauri-Ibanez C, Astigarraga I. Use of antiangiogenic therapies in pediatric solid tumors. Cancers (Basel) 2021 Jan 12;13(2):253. google scholar
• Bae ON, Noh M, Chun YJ, Jeong TC. Keratinocytic vascular endothelial growth factor as a novel biomarker for pathological skin condition. Biomol Ther (Seoul) 2015 Jan;23(1):12-8. google scholar
• Madu CO, Wang S, Madu CO, Lu Y. Angiogenesis in breast cancer progression, diagnosis, and treatment. J Cancer 2020 May 18;11(15):4474-4494. google scholar
• McMahon G. VEGF receptor signaling in tumor angiogenesis. Oncologist 2000;5 Suppl 1:3-10. google scholar
• Garcia J, Hurwitz HI, Sandler AB, Miles D, Coleman RL, Deurloo R, et al. Bevacizumab (Avastin®) in cancer treatment: A review of 15 years of clinical experience and future outlook. Cancer Treat Rev 2020 Jun;86:102017. google scholar
• Zhao Y, Adjei AA. Targeting angiogenesis in cancer therapy: Moving beyond vascular endothelial growth factor. Oncologist 2015 Jun;20(6):660-73. google scholar
• Li M, Kroetz DL. Bevacizumab-induced hypertension: Clinical presentation and molecular understanding. Pharmacol Ther 2018 Feb;182:152-160. google scholar
• Shih T, Lindley C. Bevacizumab: an angiogenesis inhibitor for the treatment of solid malignancies. Clin Ther 2006 Nov;28(11):1779-802. google scholar
• Kazazi-Hyseni F, Beijnen JH, Schellens JH. Bevacizumab. Oncologist 2010;15(8):819-25. google scholar
• Mukherji SK. Bevacizumab (Avastin). AJNR Am J Neuroradiol 2010 Feb;31(2):235-6. google scholar
• Arean C, Orellana ME, Abourbih D, Abreu C, Pifano I, Burnier MN Jr. Expression of vascular endothelial growth factor in retinoblastoma. Arch Ophthalmol 2010 Feb;128(2):223-9. google scholar
• Wen Y, Zhang W, Zhang Y, Hu H, Li J, Huang D. Short-term prognosis of childhood hepatoblastoma in relation to ERCC1 C118T single nucleotide polymorphism and VEGF expression. Pol J Pathol 2019;70(4):304-310. google scholar
• Rowe DH, Huang J, Kayton ML, Thompson R, Troxel A, O’Toole KM et al. Anti-VEGF antibody suppresses primary tumor growth and metastasis in an experimental model of Wilms’ tumor. J Pediatr Surg 2000 Jan;35(1):30-2; discussion 32-3. google scholar
• Gheytanchi E, Mehrazma M, Madjd Z. Expression of Ki-67, p53 and VEGF in pediatric neuroblastoma. Asian Pac J Cancer Prev 2014;15(7):3065-70. google scholar
• Thompson EM, Keir ST, Venkatraman T, Lascola C, Yeom KW, Nixon AB et al. The role of angiogenesis in Group 3 medulloblastoma pathogenesis and survival. Neuro Oncol 2017 Sep 1;19(9):1217-1227. google scholar
• Chen Y, Guo L, Li X, Liu R, Ren C, Du S. Reduced-dose bevacizumab vs. standard-dose bevacizumab in recurrent high-grade glioma: Which one is better? A meta-analysis. Clin Neurol Neurosurg 2020 Nov;198:106239. google scholar
• Sie M, de Bont ES, Scherpen FJ, Hoving EW, den Dunnen WF. Tumour vasculature and angiogenic profile of paediatric pilocytic astrocytoma; is it much different from glioblastoma? Neuropathol Appl Neurobiol 2010 Dec;36(7):636-47. google scholar
• Myers AL, Williams RF, Ng CY, Hartwich JE, Davidoff AM. Bevacizumab induced tumor vessel remodeling in rhabdomyosarcoma xenografts increases the effectiveness of adjuvant ionizing radiation. J Pediatr Surg 2010 Jun;45(6):1080-5. google scholar
• Turner DC, Navid F, Daw NC, Mao S, Wu J, Santana VM, et al. Population pharmacokinetics of bevacizumab in children with osteosarcoma: implications for dosing. Clin Cancer Res 2014 May 15;20(10):2783-92. google scholar
• Liu Y, Zhang F, Zhang Z, Wang D, Cui B, Zeng F et al. High expression levels of Cyr61 and VEGF are associated with poor prognosis in osteosarcoma. Pathol Res Pract 2017 Aug;213(8):895-899. google scholar
• Federico SM, Caldwell KJ, McCarville MB, Daryani VM, Stewart CF, Mao S et al. Phase I expansion cohort to evaluate the combination of bevacizumab, sorafenib and low-dose cyclophosphamide in children and young adults with refractory or recurrent solid tumours. Eur J Cancer 2020 Jun;132:35-42. google scholar
• Huang L, Jiang S, Shi Y. Tyrosine kinase inhibitors for solid tumors in the past 20 years (2001-2020). J Hematol Oncol 2020 Oct 27;13(1):143. google scholar
• da Fonseca LG, Reig M, Bruix J. Tyrosine kinase inhibitors and hepatocellular carcinoma. Clin Liver Dis 2020 Nov;24(4):719-737. google scholar
• Pignochino Y, Grignani G, Cavalloni G, Motta M, Tapparo M, Bruno S, et al. Sorafenib blocks tumour growth, angiogenesis and metastatic potential in preclinical models of osteosarcoma through a mechanism potentially involving the inhibition of ERK1/2, MCL-1 and ezrin pathways. Mol Cancer 2009 Dec 10;8:118. google scholar
• Mei J, Zhu X, Wang Z, Wang Z. VEGFR, RET, and RAF/MEK/ERK pathway take part in the inhibition of osteosarcoma MG63 cells with sorafenib treatment. Cell Biochem Biophys 2014 May;69(1):151-6. google scholar
• Lee ATJ, Jones RL, Huang PH. Pazopanib in advanced soft tissue sarcomas. Signal Transduct Target Ther 2019 May 17;4:16. google scholar
• Liu Y, Huang N, Liao S, Rothzerg E, Yao F, Li Y et al. Current research progress in targeted anti-angiogenesis therapy for osteosarcoma. Cell Prolif 2021 Sep;54(9):e13102. google scholar
• El-Khoueiry AB, Hanna DL, Llovet J, Kelley RK. Cabozantinib: An evolving therapy for hepatocellular carcinoma. Cancer Treat Rev 2021 Jul;98:102221. google scholar
• Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med 2018 Jul 5;379(1):54-63. google scholar
• Sanz-Garcia E, Sauri T, Tabernero J, Macarulla T. Pharmacokinetic and pharmacodynamic evaluation of aflibercept for the treatment of colorectal cancer. Expert Opin Drug Metab Toxicol 2015 Jun;11(6):995-1004. google scholar
• LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Ramucirumab. 2017 May 29. PMID: 31643324. google scholar
• Itatani Y, Kawada K, Yamamoto T, Sakai Y. Resistance to anti-angiogenic therapy in cancer-alterations to anti-VEGF pathway. Int J Mol Sci 2018 Apr 18;19(4):1232. google scholar
• Tabernero J, Hozak RR, Yoshino T, Cohn AL, Obermannova R, Bodoky G, et al. Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from RAISE, a global, randomized, double-blind, phase III study. Ann Oncol 2018 Mar 1;29(3):602-609. google scholar
• Gao F, Yang C. Anti-VEGF/VEGFR2 Monoclonal antibodies and their combinations with PD-1/PD-L1 inhibitors in clinic. Curr Cancer Drug Targets 2020;20(1):3-18. google scholar
• McDermott DF, Atkins MB, Motzer RJ, Rini BI, Escudier BJ, Fong L. A phase II study of atezolizumab (atezo) with or without bevacizumab (bev) versus sunitinib (sun) in untreated metastatic renal cell carcinoma (mRCC) patients (pts). J Clin Oncol 2017;35:6_suppl, 431-431 google scholar