Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
J Pathol. 2011 Apr;223(5):626-34. doi: 10.1002/path.2836. Epub 2011 Feb 21.
Currently available compounds that interfere with VEGF-A signalling effectively inhibit angiogenesis in gliomas, but influence diffuse infiltrative growth to a much lesser extent. Development of a functional tumour vascular bed not only involves VEGF-A but also requires platelet-derived growth factor receptor-β (PDGFRβ), which induces maturation of tumour blood vessels. Therefore, we tested whether combined inhibition of VEGFR and PDGFRβ increases therapeutic benefit in the orthotopic glioma xenograft models E98 and E473, both displaying the diffuse infiltrative growth that is characteristically observed in most human gliomas. We used bevacizumab and vandetanib as VEGF(R) inhibitors, and sunitinib to additionally target PDGFRβ. We show that combination therapy of sunitinib and vandetanib does not improve therapeutic efficacy compared to treatment with sunitinib, vandetanib or bevacizumab alone. Furthermore, all compounds induced reduction of vessel leakage in compact E98 tumour areas, resulting in decreased detectability of these mostly infiltrative xenografts in Gd-DTPA-enhanced MRI scans. These data show that inhibition of VEGF signalling cannot be optimized by additional PDGFR inhibition and support the concept that diffuse infiltrative areas in gliomas are resistant to anti-angiogenic therapy.
目前可用的干扰 VEGF-A 信号的化合物能有效抑制神经胶质瘤中的血管生成，但对弥漫浸润性生长的影响要小得多。功能性肿瘤血管床的形成不仅需要 VEGF-A，还需要血小板衍生生长因子受体-β（PDGFRβ），后者诱导肿瘤血管的成熟。因此，我们测试了联合抑制 VEGFR 和 PDGFRβ 是否会增加 E98 和 E473 两种神经胶质瘤异种移植模型中的治疗益处，这两种模型都表现出了在大多数人类神经胶质瘤中观察到的弥漫浸润性生长的特征。我们使用贝伐单抗和凡德他尼作为 VEGF（R）抑制剂，并使用舒尼替尼来进一步靶向 PDGFRβ。我们发现，与单独使用舒尼替尼、凡德他尼或贝伐单抗相比，舒尼替尼和凡德他尼联合治疗并不能提高治疗效果。此外，所有化合物都诱导了紧密型 E98 肿瘤区域的血管渗漏减少，从而导致 Gd-DTPA 增强 MRI 扫描中这些主要浸润性异种移植物的可检测性降低。这些数据表明，VEGF 信号的抑制不能通过额外的 PDGFR 抑制来优化，并支持弥漫浸润性胶质瘤区域对抗血管生成治疗具有抗性的概念。
