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

Year 2023, , 311 - 317, 24.10.2023

Ali Kazdal , Meryem Ertuğrul , Selma Söylemez Hikmet Gülşah Tanyıldız

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

Abstract

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.

Keywords

angiogenesis, vascular endothelial growth factor, VEGF, bevacizumab

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

Abstract

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.

Keywords

anjiyogenesis, vasküler endoteliyal büyüme faktörü, VEGF, bevacizumab

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