Abnormal morphology biases hematocrit distribution in tumor vasculature and contributes to heterogeneity in tissue oxygenation
Copyright © 2020 the Author(s). Published by PNAS..
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 [Formula: see text] and diameters [Formula: see text] from tumor allografts of three cancer cell lines and observed a substantial reduction in the ratio [Formula: see text] compared to physiological conditions. Mathematical modeling reveals that small values of the ratio λ (i.e., [Formula: see text]) can bias hematocrit distribution in tumor vascular networks and drive heterogeneous oxygenation of tumor tissue. Finally, we show an increase in the value of λ in tumor vascular networks following treatment with the antiangiogenic cancer agent DC101. Based on our findings, we propose λ 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:117 |
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| Enthalten in: |
Proceedings of the National Academy of Sciences of the United States of America - 117(2020), 45 vom: 10. Nov., Seite 27811-27819 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Bernabeu, Miguel O [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 07.01.2021 Date Revised 07.01.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1073/pnas.2007770117 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM316783900 |
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| 100 | 1 | |a Bernabeu, Miguel O |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Abnormal morphology biases hematocrit distribution in tumor vasculature and contributes to heterogeneity in tissue oxygenation |
| 264 | 1 | |c 2020 | |
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| 500 | |a Date Revised 07.01.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2020 the Author(s). Published by PNAS. | ||
| 520 | |a 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 [Formula: see text] and diameters [Formula: see text] from tumor allografts of three cancer cell lines and observed a substantial reduction in the ratio [Formula: see text] compared to physiological conditions. Mathematical modeling reveals that small values of the ratio λ (i.e., [Formula: see text]) can bias hematocrit distribution in tumor vascular networks and drive heterogeneous oxygenation of tumor tissue. Finally, we show an increase in the value of λ in tumor vascular networks following treatment with the antiangiogenic cancer agent DC101. Based on our findings, we propose λ 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a anti-angiogenic agents | |
| 650 | 4 | |a hematocrit dynamics | |
| 650 | 4 | |a mathematical modelling | |
| 650 | 4 | |a oxygen heterogeneity | |
| 650 | 4 | |a tumor vasculature | |
| 650 | 7 | |a Angiogenesis Inhibitors |2 NLM | |
| 650 | 7 | |a Biomarkers, Tumor |2 NLM | |
| 650 | 7 | |a Oxygen |2 NLM | |
| 650 | 7 | |a S88TT14065 |2 NLM | |
| 700 | 1 | |a Köry, Jakub |e verfasserin |4 aut | |
| 700 | 1 | |a Grogan, James A |e verfasserin |4 aut | |
| 700 | 1 | |a Markelc, Bostjan |e verfasserin |4 aut | |
| 700 | 1 | |a Beardo, Albert |e verfasserin |4 aut | |
| 700 | 1 | |a d'Avezac, Mayeul |e verfasserin |4 aut | |
| 700 | 1 | |a Enjalbert, Romain |e verfasserin |4 aut | |
| 700 | 1 | |a Kaeppler, Jakob |e verfasserin |4 aut | |
| 700 | 1 | |a Daly, Nicholas |e verfasserin |4 aut | |
| 700 | 1 | |a Hetherington, James |e verfasserin |4 aut | |
| 700 | 1 | |a Krüger, Timm |e verfasserin |4 aut | |
| 700 | 1 | |a Maini, Philip K |e verfasserin |4 aut | |
| 700 | 1 | |a Pitt-Francis, Joe M |e verfasserin |4 aut | |
| 700 | 1 | |a Muschel, Ruth J |e verfasserin |4 aut | |
| 700 | 1 | |a Alarcón, Tomás |e verfasserin |4 aut | |
| 700 | 1 | |a Byrne, Helen M |e verfasserin |4 aut | |
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