Department of Radiation Oncology, Massachusetts General Hospital & Massachusetts Institute of Technology, Boston, Massachusetts 02114, USA.
Cancer Res. 2011 Jan 1;71(1):19-28. doi: 10.1158/0008-5472.CAN-10-2602.
Recurrent glioblastomas (rGBM) invariably relapse after initial response to anti-VEGF therapy. There are 2 prevailing hypotheses on how these tumors escape antiangiogenic therapy: switch to VEGF-independent angiogenic pathways and vessel co-option. However, direct evidence in rGBM patients is lacking. Thus, we compared molecular, cellular, and vascular parameters in autopsy tissues from 5 rGBM patients who had been treated with the pan-VEGF receptor tyrosine kinase inhibitor cediranib versus 7 patients who received no therapy or chemoradiation but no antiangiogenic agents. After cediranib treatment, endothelial proliferation and glomeruloid vessels were decreased, and vessel diameters and perimeters were reduced to levels comparable to the unaffected contralateral brain hemisphere. In addition, tumor endothelial cells expressed molecular markers specific to the blood-brain barrier, indicative of a lack of revascularization despite the discontinuation of therapy. Surprisingly, in cediranib-treated GBM, cellular density in the central area of the tumor was lower than in control cases and gradually decreased toward the infiltrating edge, indicative of a change in growth pattern of rGBMs after cediranib treatment, unlike that after chemoradiation. Finally, cediranib-treated GBMs showed high levels of PDGF-C (platelet-derived growth factor C) and c-Met expression and infiltration by myeloid cells, which may potentially contribute to resistance to anti-VEGF therapy. In summary, we show that rGBMs switch their growth pattern after anti-VEGF therapy--characterized by lower tumor cellularity in the central area, decreased pseudopalisading necrosis, and blood vessels with normal molecular expression and morphology--without a second wave of angiogenesis.
复发性胶质母细胞瘤（rGBM）在初始抗血管内皮生长因子（VEGF）治疗后不可避免地会复发。目前有两种主流假说解释这些肿瘤如何逃避抗血管生成治疗：一是切换到 VEGF 非依赖性血管生成途径和血管选择；二是血管生成拟态。然而，在 rGBM 患者中缺乏直接证据。因此，我们比较了 5 例接受 pan-VEGF 受体酪氨酸激酶抑制剂 cediranib 治疗和 7 例未接受治疗或放化疗但未接受抗血管生成药物治疗的 rGBM 患者尸检组织的分子、细胞和血管参数。cediranib 治疗后，内皮细胞增殖和肾小球样血管减少，血管直径和周长减小到与未受影响的对侧大脑半球相当的水平。此外，肿瘤内皮细胞表达血液-脑屏障的特异性分子标志物，表明尽管停止治疗，但不存在再血管化。令人惊讶的是，在 cediranib 治疗的 GBM 中，肿瘤中央区域的细胞密度低于对照组，并逐渐向浸润边缘减少，这表明 cediranib 治疗后 rGBM 的生长模式发生了变化，与放化疗后不同。最后，cediranib 治疗的 GBM 表现出高水平的血小板衍生生长因子 C（PDGF-C）和 c-Met 表达以及髓样细胞浸润，这可能有助于抵抗抗 VEGF 治疗。总之，我们表明 rGBM 在抗 VEGF 治疗后改变了其生长模式——表现为中央区域肿瘤细胞密度降低、假栅状坏死减少以及血管具有正常的分子表达和形态，而没有第二次血管生成。
