Publication: Vestibüler Schwannoma Tümörleri üzerinde İmatinib’in Anti-Anjiojenik etkilerinin İn Vivo Korneal Anjiojenez Modeli ile gösterilmesi
Abstract
Vestibüler schwannomalar (VS) tüm intrakranial tümörlerin %8-10 unun oluşturmaktadır ve serebellopontin köşeye lokalize, histopatolojik olarak iyi huylu, yavaş büyüyen Obersteiner-Redlich zonunundaki neoplazik transformasyondan köken alan tümörlerdir. VS hastalarında tedavinin amacı, tümörün büyüklüğüne bağlı olarak total eksizyon veya radyocerrahi ile tümör kontrolünün sağlanmasıdır. Ancak cerrahi olarak total eksizyon uygulandığında tümörün büyüklüğü ile orantılı olarak hastada morbidite oranı artmaktadır. Bu çalışmanın amacı bir anti-anjiojenik ajan olan imatinibin, sporadik VS ve Nörofibromatozis tip-II (NF-II) VS hastalarındaki etkilerinin in vivo korneal anjiojenez modeli kullanılarak anjiojenez üzerine etkinliğinin incelemesidir. Çalışmada Marmara Üniversitesi Tıp Fakültesi Hastanesi ve Marmara Üniversitesi Nörolojik Bilimler Enstitüsünde 1991-2010 tarihleri arasında opere edilmiş sporadik VS ve NF-II VS hastaları retrospektif olarak incelenmiştir. Deneysel çalışmada tümör bankasından alınan uygun nitelikteki 6 sporadik VS dokusu ile 4 NF-II VS dokusu kullanılmıştır. Çalışmada, kullanılan dokuların immünohistokimyasal, western blot ve in vivo korneal anjiojenez modellemeleri ile imatinib kullanılarak ve kullanılmadan anjiojenik kapasiteleri karşılaştırılmıştır. Sonuçta, sporadik VS ve NF-II VS dokularının in vivo korneal anjiojenezde normal dokulara oranla anjiojenez yeteneklerinin daha fazla olduğu görülmüştür. Ayrıca sporadik VS dokusunun NF-II VS dokusuna göre anjiojenik potansiyelinin daha fazla olduğu izlenmiştir. İmmünohistokimyasal olarak her iki doku grubunda da anjiojenezin yol ağı olan PDGF ligand ve reseptörlerinde ekspresyon artışı görülmüştür ve bu bulgu western blot tekniği ile doğrulanmıştır. İmatinibin etki gösterdiği PDGFR-B ekspresyonunun, sporadik VSlerde immunohistokimyasal olarak anlamlı derece arttığı görülmüştür. Buna paralel olarak korneal anjiojenez modelinde sporadik VSlerin anjiojenezinin imatinib tarafından anlamlı derecede azaltıldığı izlenmiştir. Sonuç olarak elde ettiğimiz bulgular sporadik VS tümörlerinin tedavisinde, cerrahi ve radyocerrahi tedaviye ek olarak, antianjiojenik moleküller ile medikal tedavinin uygulanabileceğini düşündürmektedir. PDGF yol ağının etkinliğinin gösterilmesi ve bu yolun anjiojenezinin antianjiojenik moleküller ile inhibe edilmesi sonucunda tümörün büyümesinin önüne geçilebileceğini düşünmekteyiz. ANAHTAR SÖZCÜKLER: Vestibüler Schwannoma, NF-II, Anjiojenez, İmatinib, Kornea modeli
Vestibular schwannomas (VSs) constitute 8-10% of all intracranial tumors. They are benign and slow growing tumors. Moreover, they are localized in cerebellopontin angle (CPA) and originated from the neoplastic transformation in the Obersteiner- Redlich zone. The treatment objective of VS patients is to ensure the control of tumor growth by either total excision or radiosurgery of the tumor, depending on the tumor size. However, the total excision of the tumor increases the morbidity rate depending on the size of the tumor. The aim of this study is to investigate the effect of an antiangiogenic agent, called imatinib, on angiogenesis in sporadic VS and NF-II VS patients by using the in vivo corneal angionesis model. In the present study, the sporadic VS and NF-II VS patients who were operated in University of Marmara, Medical School Hospital and University of Marmara, Institute of Neurological Sciences between 1991 and 2010, were inspected restrospectively. In the experimental study, 6 sporadic VS and NF-II VS tissues taken from the tumor bank were used. The angiogenic capacities of the tissues were compared by performing the immunohistochemical, western blot and in vivo corneal angionesis models either with the use of imatinib or without the use of imatinib. The results of the study show that the sporadic VS and NF-II VS tissues have more angiogenetic ability than normal tissues in vivo corneal angionesis. In addition, the sporadic VS tissues are shown to have more angiogenic potential than NF-II VS tissues. Immunohistochemically, both tissue groups showed an increase in the expression of receptors and ligands of PDGF, which is the pathway of angionesis and this finding is confirmed by the western blot technic. The expression of PDGFR-B, which is influenced by imatinib, is shown to be immunohistochemically increased in sporadic VSs. In parallel with this finding, the angionesis of sporadic VSs is found to be significantly reduced by imatinib in corneal angionesis model. In conclusion, the findings of this study show that the medical treatment with the use of antiangiogenic molecules can be an extra treatment option in addition to excision and radiosurgery. We believe that with the effect of PDGF pathway and the inhibition of angiogenesis of this pathway with the use of antiangiogenic molecules, the growth of tumor can be controlled. KEY WORDS: Vestibular Schwannoma, NF-II, Angiogenesis, Imatinib, Corneal model
Vestibular schwannomas (VSs) constitute 8-10% of all intracranial tumors. They are benign and slow growing tumors. Moreover, they are localized in cerebellopontin angle (CPA) and originated from the neoplastic transformation in the Obersteiner- Redlich zone. The treatment objective of VS patients is to ensure the control of tumor growth by either total excision or radiosurgery of the tumor, depending on the tumor size. However, the total excision of the tumor increases the morbidity rate depending on the size of the tumor. The aim of this study is to investigate the effect of an antiangiogenic agent, called imatinib, on angiogenesis in sporadic VS and NF-II VS patients by using the in vivo corneal angionesis model. In the present study, the sporadic VS and NF-II VS patients who were operated in University of Marmara, Medical School Hospital and University of Marmara, Institute of Neurological Sciences between 1991 and 2010, were inspected restrospectively. In the experimental study, 6 sporadic VS and NF-II VS tissues taken from the tumor bank were used. The angiogenic capacities of the tissues were compared by performing the immunohistochemical, western blot and in vivo corneal angionesis models either with the use of imatinib or without the use of imatinib. The results of the study show that the sporadic VS and NF-II VS tissues have more angiogenetic ability than normal tissues in vivo corneal angionesis. In addition, the sporadic VS tissues are shown to have more angiogenic potential than NF-II VS tissues. Immunohistochemically, both tissue groups showed an increase in the expression of receptors and ligands of PDGF, which is the pathway of angionesis and this finding is confirmed by the western blot technic. The expression of PDGFR-B, which is influenced by imatinib, is shown to be immunohistochemically increased in sporadic VSs. In parallel with this finding, the angionesis of sporadic VSs is found to be significantly reduced by imatinib in corneal angionesis model. In conclusion, the findings of this study show that the medical treatment with the use of antiangiogenic molecules can be an extra treatment option in addition to excision and radiosurgery. We believe that with the effect of PDGF pathway and the inhibition of angiogenesis of this pathway with the use of antiangiogenic molecules, the growth of tumor can be controlled. KEY WORDS: Vestibular Schwannoma, NF-II, Angiogenesis, Imatinib, Corneal model