Tumor recovery by angiogenic switch from sprouting to intussusceptive angiogenesis after treatment with PTK787/ZK222584 or ionizing radiation
Tumor recovery by angiogenic switch from sprouting to intussusceptive angiogenesis after treatment with PTK787/ZK222584 or ionizing radiation
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DOI：
10.2353/ajpath.2008.071131
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发表时间：
2008-10-01
影响因子：
6
通讯作者：
Djonov, Valentin
中科院分区：
文献类型：
--
作者：
Hlushchuk, Ruslan;Riesterer, Oliver;Djonov, Valentin
血管生成抑制剂和放疗在治疗停止期间和之后诱导肿瘤血管代偿性变化。为了评估辐照和血管内皮生长因子受体酪氨酸激酶抑制（由血管内皮生长因子酪氨酸激酶抑制剂PYK787/ZK222854）的反应，血管铸型研究了乳腺癌同种异体移植物；电子显微镜、光学显微镜和共聚焦显微镜；和免疫印迹。放射治疗和抗血管生成治疗对肿瘤血管系统的影响相似。两种治疗方法都减少了肿瘤的血管化，尤其是肿瘤髓质的血管化。停止治疗后，肿瘤血管主要以肠套叠扩张，形成由扩大的窦状血管组成的神经丛，其中含有多个腔内组织柱。肿瘤血运重建起源于肿瘤皮层保存的α -平滑肌肌动蛋白阳性血管。定量显示恢复的特征是血管生成从发芽到肠套叠的转换。恢复过程中α -平滑肌肌动蛋白表达的上调反映了α -平滑肌肌动蛋白阳性细胞在肠套叠中的募集，这是血管适应机制的一部分。肿瘤恢复与肿瘤内微血管密度的急剧下降（30%至40%）有关，这可能是肠套敏感性修剪的结果，令人惊讶的是，总微血管（交换）面积只有最小的减少。因此，正如缺氧诱导因子-1 α的表达所证明的那样，肿瘤的血管供应没有严重受损。照射和抗血管生成治疗都会导致从萌芽到肠套接血管生成的转变，这是一种逃逸机制，可以解释耐药性的发展以及停止治疗后的快速恢复。
Inhibitors of angiogenesis and radiation induce compensatory changes in the tumor vasculature both during and after treatment cessation. To assess the responses to irradiation and vascular endothelial growth factor-receptor tyrosine kinase inhibition (by the vascular endothelial growth factor tyrosine kinase inhibitor PYK787/ZK222854), mammary carcinoma allografts were investigated by vascular casting; electron, light, and confocal microscopy; and immunoblotting. Irradiation and anti-angiogenic therapy had similar effects on the tumor vasculature. Both treatments reduced tumor vascularization, particularly in the tumor medulla. After cessation of therapy, the tumor vasculature expanded predominantly by intussusception with a plexus composed of enlarged sinusoidal-like vessels containing multiple transluminal tissue pillars. Tumor revascularization originated from preserved alpha-smooth muscle actin-positive vessels in the tumor cortex. Quantification revealed that recovery was characterized by an angiogenic switch from sprouting to intussusception. Up-regulated alpha-smooth muscle actin-expression during recovery reflected the recruitment of alpha-smooth muscle actin-positive cells for intussusception as part of the angio-adaptive mechanism. Tumor recovery was associated with a dramatic decrease (by 30% to 40%) in the intratumoral microvascular density, probably as a result of intussusceptive pruning and, surprisingly, with only a minimal reduction of the total microvascular (exchange) area. Therefore, the vascular supply to the tumor was not severely compromised, as demonstrated by hypoxia-inducible factor-1 alpha expression. Both irradiation and anti-angiogenic therapy cause a switch from sprouting to intussusceptive angiogenesis, representing an escape mechanism and accounting for the development of resistance, as well as rapid recovery, after cessation of therapy.