Multiphoton Phosphorescence Quenching Microscopy Reveals Kinetics of Tumor Oxygenation during Antiangiogenesis and Angiotensin Signaling Inhibition.
Multiphoton Phosphorescence Quenching Microscopy Reveals Kinetics of Tumor Oxygenation during Antiangiogenesis and Angiotensin Signaling Inhibition.
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DOI：
10.1158/1078-0432.ccr-22-0486
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发表时间：
2022-07-15
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影响因子：
--
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中科院分区：
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肿瘤血管功能异常导致组织缺氧，促进疾病进展和治疗抵抗。尽管肿瘤微环境正常化策略可以在全球范围内缓解缺氧，但由于无法以足够的分辨率纵向评估肿瘤中的血管和间质氧气，局部氧气水平如何变化尚不清楚。了解空间和时间的异质性应该有助于改善各种标准化策略的结果。我们开发了一种多光子磷光淬灭显微镜系统，使用低分子量钯卟啉探针测量灌注血管，氧张力，以及它们在小鼠皮肤，骨髓和四种不同的肿瘤模型中的空间相关性。此外，我们测量了肿瘤中氧气和血管灌注的时间和空间变化，以响应抗VEGFR2抗体（DC101）和血管紧张素受体阻断剂（氯沙坦）。我们发现血管功能高度依赖于肿瘤类型。虽然有些肿瘤的血管比正常皮肤的血管具有更大的携氧能力，但大多数肿瘤的血管效率低下。此外，肿瘤中的血管间异质性与对DC 101和洛沙坦的异质性反应有关。使用血管和基质正常化剂，我们表明，空间异质性的氧水平持续存在，即使减少平均血管外缺氧。肿瘤血管对两种已知可改善血管灌注的药物的高分辨率空间和时间响应显示了血管结构和功能的空间异质性变化。在优化血管和基质正常化策略的剂量和时间表以改善治疗结果时，应考虑这些动态血管变化。
The abnormal function of tumor blood vessels causes tissue hypoxia, promoting disease progression and treatment resistance. Although tumor microenvironment normalization strategies can alleviate hypoxia globally, how local oxygen levels change is not known because of the inability to longitudinally assess vascular and interstitial oxygen in tumors with sufficient resolution. Understanding the spatial and temporal heterogeneity should help improve the outcome of various normalization strategies. We developed a multiphoton phosphorescence quenching microscopy system using a low-molecular-weight palladium porphyrin probe to measure perfused vessels, oxygen tension, and their spatial correlations in vivo in mouse skin, bone marrow, and four different tumor models. Further, we measured the temporal and spatial changes in oxygen and vessel perfusion in tumors in response to an anti-VEGFR2 antibody (DC101) and an angiotensin-receptor blocker (losartan). We found that vessel function was highly dependent on tumor type. Although some tumors had vessels with greater oxygen-carrying ability than those of normal skin, most tumors had inefficient vessels. Further, intervessel heterogeneity in tumors is associated with heterogeneous response to DC101 and losartan. Using both vascular and stromal normalizing agents, we show that spatial heterogeneity in oxygen levels persists, even with reductions in mean extravascular hypoxia. High-resolution spatial and temporal responses of tumor vessels to two agents known to improve vascular perfusion globally reveal spatially heterogeneous changes in vessel structure and function. These dynamic vascular changes should be considered in optimizing the dose and schedule of vascular and stromal normalizing strategies to improve the therapeutic outcome.
影响因子：
3.7
作者：
Ricard C;Stanchi F;Rodriguez T;Amoureux MC;Rougon G;Debarbieux F
通讯作者：
Debarbieux F