Abnormal morphology biases hematocrit distribution in tumor vasculature and contributes to heterogeneity in tissue oxygenation.
Abnormal morphology biases hematocrit distribution in tumor vasculature and contributes to heterogeneity in tissue oxygenation.
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DOI：
10.1073/pnas.2007770117
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发表时间：
2020-11-10
影响因子：
11.1
通讯作者：
Byrne HM
中科院分区：
文献类型：
--
作者：
Bernabeu MO;Köry J;Grogan JA;Markelc B;Beardo A;d'Avezac M;Enjalbert R;Kaeppler J;Daly N;Hetherington J;Krüger T;Maini PK;Pitt-Francis JM;Muschel RJ;Alarcón T;Byrne HM
实体肿瘤的氧异质性被认为是影响治疗效果的一个限制因素。这种异质性源于肿瘤血管结构的异常。我们研究了红细胞运输异常在肿瘤组织中氧异质性的建立中所起的作用。我们引入了一个度量来表征肿瘤血管系统（平均血管长度与直径比），并演示了它如何预测组织氧异质性。我们还报道了抗血管生成药物DC101的后续治疗增加。总之，我们提出了一种有效的方法来监测抗血管生成药物的作用和替代测量肿瘤组织中的氧异质性。揭示肿瘤血管结构和组织氧合之间的因果关系将为新的个性化治疗方法铺平道路。实体肿瘤的氧异质性被认为是影响治疗效果的一个限制因素。这种异质性源于肿瘤的异常血管结构，但连接异常结构和氧气运输受损的确切机制仅部分了解。在本文中，我们研究了红细胞（RBC）运输在肿瘤组织中建立氧异质性的作用。我们关注由网络效应驱动的异质性，由于通常考虑的视野减少，因此在实验中观察网络效应具有挑战性。由于我们发现与当前红细胞运输理论偏差相关的异常血管模式，我们计算了三种癌细胞系肿瘤同种异体移植物的平均血管长度和直径，并观察到与生理条件相比，这一比例大幅降低。数学模型显示，该比值的小值（即）可以使肿瘤血管网络中的红细胞压积分布偏倚，并驱动肿瘤组织的非均质氧合。最后，我们显示抗血管生成癌症药物DC101治疗后肿瘤血管网络的价值增加。基于我们的研究结果，我们提出了一种有效的方法来监测抗血管生成药物的疗效，并作为抗血管生成治疗的肿瘤组织灌注和氧合的替代指标。
Oxygen heterogeneity in solid tumors is recognized as a limiting factor for therapeutic efficacy. This heterogeneity arises from the abnormal tumor vascular structure. We investigate the role that anomalies in red blood cell transport plays in establishing oxygen heterogeneity in tumor tissue. We introduce a metric to characterize tumor vasculature (mean vessel length-to-diameter ratio, ) and demonstrate how it predicts tissue-oxygen heterogeneity. We also report an increase in following treatment with the antiangiogenic agent DC101. Together, we propose as an effective way of monitoring the action of antiangiogenic agents and a proxy measure of oxygen heterogeneity in tumor tissue. Unraveling the causal relationship between tumor vascular structure and tissue oxygenation will pave the way for new personalized therapeutic approaches. Oxygen heterogeneity in solid tumors is recognized as a limiting factor for therapeutic efficacy. This heterogeneity arises from the abnormal vascular structure of the tumor, but the precise mechanisms linking abnormal structure and compromised oxygen transport are only partially understood. In this paper, we investigate the role that red blood cell (RBC) transport plays in establishing oxygen heterogeneity in tumor tissue. We focus on heterogeneity driven by network effects, which are challenging to observe experimentally due to the reduced fields of view typically considered. Motivated by our findings of abnormal vascular patterns linked to deviations from current RBC transport theory, we calculated average vessel lengths and diameters from tumor allografts of three cancer cell lines and observed a substantial reduction in the ratio compared to physiological conditions. Mathematical modeling reveals that small values of the ratio (i.e., ) can bias hematocrit distribution in tumor vascular networks and drive heterogeneous oxygenation of tumor tissue. Finally, we show an increase in the value of in tumor vascular networks following treatment with the antiangiogenic cancer agent DC101. Based on our findings, we propose as an effective way of monitoring the efficacy of antiangiogenic agents and as a proxy measure of perfusion and oxygenation in tumor tissue undergoing antiangiogenic treatment.
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影响因子：
3.4
作者：
Bernabeu MO;Jones ML;Nash RW;Pezzarossa A;Coveney PV;Gerhardt H;Franco CA
通讯作者：
Franco CA
影响因子：
3.7
作者：
Doyeux, V.;Podgorski, T.;Coupier, G.
通讯作者：
Coupier, G.
影响因子：
48
作者：
Kamoun, Walid S.;Chae, Sung-Suk;Lacorre, Delphine A.;Tyrrell, James A.;Mitre, Mariela;Gillissen, Marijn A.;Fukumura, Dai;Jain, Rakesh K.;Munn, Lance L.
通讯作者：
Munn, Lance L.
影响因子：
3.4
作者：
Grogan, James A.;Connor, Anthony J.;Pitt-Francis, Joe M.
通讯作者：
Pitt-Francis, Joe M.
影响因子：
4.6
作者：
Grogan, James A.;Markelc, Bostjan;Byrne, Helen M.
通讯作者：
Byrne, Helen M.