Continuous delivery of IFN-β promotes sustained maturation of intratumoral vasculature
Continuous delivery of IFN-β promotes sustained maturation of intratumoral vasculature
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DOI：
10.1158/1541-7786.mcr-06-0259
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发表时间：
2007-06-01
影响因子：
5.2
通讯作者：
Davidoff, Andrew M.
中科院分区：
文献类型：
--
作者：
Dickson, Paxton V.;Hamner, John B.;Davidoff, Andrew M.
IFN具有多效性抗肿瘤作用机制。本研究的目的是进一步研究IFN-β对免疫缺陷小鼠中人异种移植物血管的影响。我们发现，用肝靶向腺相关病毒载体建立的连续、全身性IFN-β递送导致肿瘤血管系统持续的形态和功能变化，这些变化与血管成熟一致。这些变化包括肿瘤血管的平滑肌细胞覆盖增加，肿瘤内血流改善，血管通透性降低，肿瘤间质压和肿瘤内缺氧。尽管肿瘤脉管系统中的这些变化导致更有效的肿瘤灌注，但进一步的肿瘤生长受到限制，因为成熟的脉管系统似乎无法扩展以支持进一步的肿瘤生长。此外，肿瘤内脉管系统的成熟导致全身给药化疗的肿瘤内渗透增加。最后，分子分析显示血管生成素-1（一种已知促进血管稳定的细胞因子）的治疗肿瘤表达增加。在不同的肿瘤细胞系中广泛观察到IFN-β诱导血管生成素-1表达，但在IFN信号传导缺陷的肿瘤细胞系中没有观察到。此外，当用诱饵受体阻断血管生成素信号传导时，IFN-β介导的血管变化被阻止。因此，我们已经确定了一种实现持续血管重塑的替代方法-连续递送IFN-β。除了通过抑制进一步的血管生成来限制肿瘤生长之外，肿瘤脉管系统的成熟还提高了辅助治疗的递送效率。这些结果对联合抗癌治疗的规划具有重要意义。
IFNs have pleiotropic antitumor mechanisms of action. The purpose of this study was to further investigate the effects of IFN-beta on the vasculature of human xenografts in immunodeficient mice. We found that continuous, systemic IFN-beta delivery, established with liver-targeted adeno-associated virus vectors, led to sustained morphologic and functional changes of the tumor vasculature that were consistent with vessel maturation. These changes included increased smooth muscle cell coverage of tumor vessels, improved intratumoral blood flow, and decreased vessel permeability, tumor interstitial pressure, and intratumoral hypoxia. Although these changes in the tumor vasculature resulted in more efficient tumor perfusion, further tumor growth was restricted, as the mature vasculature seemed to be unable to expand to support further tumor growth. In addition, maturation of the intratumoral vasculature resulted in increased intratumoral penetration of systemically administered chemotherapy. Finally, molecular analysis revealed increased expression by treated tumors of anglopoietin-1, a cytokine known to promote vessel stabilization. Induction of anglopoietin-1 expression in response to IFN-beta was broadly observed in different tumor lines but not in those with defects in IFN signaling. In addition, IFN-beta-mediated vascular changes were prevented when anglopoietin signaling was blocked with a decoy receptor. Thus, we have identified an alternative approach for achieving sustained vascular remodeling-continuous delivery of IFN-beta. In addition to restricting tumor growth by inhibiting further angiogenesis, maturation of the tumor vasculature also improved the efficiency of delivery of adjuvant therapy. These results have significant implications for the planning of combination anticancer therapy.