Resistance to antiangiogenic therapy is directed by vascular phenotype, vessel stabilization, and maturation in malignant melanoma.
Resistance to antiangiogenic therapy is directed by vascular phenotype, vessel stabilization, and maturation in malignant melanoma.
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DOI：
10.1084/jem.20091846
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发表时间：
2010-03-15
期刊：
影响因子：
--
通讯作者：
Schadendorf D
中科院分区：
文献类型：
--
作者：
Helfrich I;Scheffrahn I;Bartling S;Weis J;von Felbert V;Middleton M;Kato M;Ergün S;Augustin HG;Schadendorf D
血管生成不仅依赖于内皮细胞的侵袭和增殖，还需要周细胞覆盖血管芽以稳定血管壁。迄今为止，针对血管内皮生长因子（VEGF）信号通路的血管生成抑制剂的临床疗效仍然有限。我们假设血管成熟水平在抗血管生成治疗反应中起关键作用。为了验证这一假设，我们在使用PTK787/ZK222584进行抗vegf治疗后，评估了MT/ret转基因小鼠自发发生黑色素瘤的血管网络，同时也分析了在接受贝伐单抗辅助治疗的患者的临床复发时发生的人类黑色素瘤转移。两项实验均表明，肿瘤血管对抗vegf治疗具有耐药性，其特征是血管直径增大，血管床正常化，包括成熟周细胞的覆盖以及desmin、NG-2、血小板衍生生长因子受体β和晚期成熟标志物α平滑肌肌动蛋白的免疫反应性。我们的研究结果强调，壁细胞分化水平和血管壁的稳定显著有助于黑色素瘤抗血管生成治疗的反应。这项研究可能有助于为第二代抗血管生成联合疗法的更合理发展铺平道路，并首次提供小鼠模型来研究这一点。
Angiogenesis is not only dependent on endothelial cell invasion and proliferation, it also requires pericyte coverage of vascular sprouts for stabilization of vascular walls. Clinical efficacy of angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signaling pathway is still limited to date. We hypothesized that the level of vessel maturation is critically involved in the response to antiangiogenic therapies. To test this hypothesis, we evaluated the vascular network in spontaneously developing melanomas of MT/ret transgenic mice after using PTK787/ZK222584 for anti-VEGF therapy but also analyzed human melanoma metastases taken at clinical relapse in patients undergoing adjuvant treatment using bevacizumab. Both experimental settings showed that tumor vessels, which are resistant to anti-VEGF therapy, are characterized by enhanced vessel diameter and normalization of the vascular bed by coverage of mature pericytes and immunoreactivity for desmin, NG-2, platelet-derived growth factor receptor β, and the late-stage maturity marker α smooth muscle actin. Our findings emphasize that the level of mural cell differentiation and stabilization of the vascular wall significantly contribute to the response toward antiangiogenic therapy in melanoma. This study may be useful in paving the way toward a more rational development of second generation antiangiogenic combination therapies and in providing, for the first time, a murine model to study this.
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