Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors
Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors
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DOI：
10.1016/j.ccr.2005.09.005
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发表时间：
2005-10-01
期刊：
影响因子：
50.3
通讯作者：
Hanahan, D
中科院分区：
文献类型：
--
作者：
Casanovas, O;Hicklin, DJ;Hanahan, D
VEGF受体R1和R2的功能阻断抗体被用来探测它们在控制胰岛癌发生的小鼠模型中的血管生成中的作用。抑制VEGFR2而不是VEGFR1显著破坏血管生成转换、持续血管生成和初始肿瘤生长。在晚期肿瘤中，出现了对VEGFR2阻断的表型抗性，因为肿瘤在生长抑制的初始阶段之后在治疗期间重新生长。这种对VEGF阻断的抗性涉及肿瘤血管生成的再活化，其独立于VEGF并且与低氧介导的其他促血管生成因子（包括FGF家族成员）的诱导相关。这些其他促血管生成信号在功能上与逃避期肿瘤的血管再生和再生长有关，因为FGF阻断会在VEGF抑制的情况下损害进展。
Function-blocking antibodies to VEGF receptors R1 and R2 were used to probe their roles in controlling angiogenesis in a mouse model of pancreatic islet carcinogenesis. Inhibition of VEGFR2 but not VEGFR1 markedly disrupted angiogenic switching, persistent angiogenesis, and initial tumor growth. In late-stage tumors, phenotypic resistance to VEGFR2 blockade emerged, as tumors regrew during treatment after an initial period of growth suppression. This resistance to VEGF blockade involves reactivation of tumor angiogenesis, independent of VEGF and associated with hypoxia-mediated induction of other proangiogenic factors, including members of the FGF family. These other proangiogenic signals are functionally implicated in the revascularization and regrowth of tumors in the evasion phase, as FGF blockade impairs progression in the face of VEGF inhibition.