Investigating tumour suppressor mutations in GBM which impact on tumour angiogenesis

GBM是一种侵袭性和高度血管生成的肿瘤，起源于肿瘤性神经前体细胞（NPC）。绝大多数原发性GBM是由关键肿瘤抑制基因的基因突变驱动的，伴随着不同原癌基因的加速活性。通过这些驱动胶质瘤发生的关键信号转导途径，可以识别出不同的肿瘤亚型，这些亚型在预后和治疗特征上不同，现在被称为前神经性、经典性或间质性。以前，我们确定VEGF-A是小鼠和人NPC的肿瘤源性化学引诱物和增殖因子。我们目前的初步结果表明，（VEGF反应性）NPC的肿瘤转化将这些生理干细胞转化为血管生成（VEGF分泌）GBM细胞。我们的初步研究表明，在小鼠和人GBM细胞中存在一致的GBM亚型特异性血管生成模式。在前神经GBM中，p53状态似乎是决定促血管生成信号分子如VEGF-A表达水平的重要因素，而VEGF-C/VEGFR 3信号可以构成其余GBM亚型的治疗靶点。因此，我们将研究GBM中不同的遗传标记物是否对个体化抗血管生成治疗具有预测能力。为此，我们已经建立了GBM活检和转基因小鼠，原位植入模型和转基因小鼠系的亚型特异性细胞培养物，用于产生GBM。这些模型的表型和遗传分析将表明GBM亚型和p53状态与GBM血管生成程度和特定血管生成信号通路的关系。将在体外和体内探索VEGFR 2或VEGFR 3阻断对不同GBM亚型的治疗影响。在使用VEGF-A阻断剂贝伐珠单抗进行抗血管生成治疗临床失败后，建议限制VEGF-A阻断剂贝伐珠单抗应用于患有前神经GBM的患者。确定前神经GBM中的p53状态是否为可能从贝伐珠单抗应用中获益的患者提供了一个精确的标志物，这将是一个有趣的问题。此外，我们的实验也适合于为患有经典或间充质GBM亚型的GBM患者确定新的治疗策略。

GBM are invasive and highly angiogenic tumours that origin from neoplastic neural precursor cells (NPCs). The vast majority of primary GBM is driven by genetic mutation in key tumour suppressor genes concomitant with accelerated activity of different proto‐oncogenes. With these key signal transduction pathways driving gliomagenesis separate tumour‐subtypes, which differ in prognosis and treatment characteristics, could be identified and are now termed proneural, classical or mesenchymal. Previously, we identified VEGF‐A as a tumour‐derived chemoattractant and proliferative factor for mouse and human NPCs. Our current preliminary results indicate that neoplastic transformation of (VEGFresponsive) NPCs converts these physiological stem cells into angiogenic (VEGF‐secreting) GBM cells.Our pilot studies suggest that consistent GBM‐subtype specific angiogenic patterns exist in mouse‐ and human‐GBM cells. In proneural GBM the p53‐status appears to be an important factor determining the expression levels of proangiogenic signalling molecules like VEGF‐A, while VEGF‐C/VEGFR3 signalling can constitute a therapeutic target for the remaining GBM‐subtypes. Consequently, we will investigate if distinct genetic markers in GBM have predictive power for individualised anti‐angiogenic treatment. Towards this end we have established subtype‐specific cell‐cultures from GBM‐biopsies and also from transgenic mice, orthotopic implantation models and transgenic mouse lines for the generation of GBM. Phenotypic and genetic analysis of these models will indicate the relation of GBM‐subtypes and p53‐status with the extent of GBM‐angiogenesis and with specific angiogenic signalling pathways. The therapeutic impact of VEGFR2 or VEGFR3‐blockade in different GBM subtypes will be explored in vitro and in vivo. After the clinical failure of anti‐angiogenic treatment using the VEGF‐A blocker bevacizumab it was suggested to restrict the application of the VEGF‐A blocker bevacizumab to patients suffering from proneural GBM. It will be interesting to determine if the p53‐status in proneural GBM provides a refined marker for patients potentially profiting from bevacizumab application. In addition our experiments are also suited to identify new therapeutic strategies for GBM‐patients suffering from the classical or mesenchymal GBM‐subtype.