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Abnormal morphology biases haematocrit distribution in tumour vasculature and contributes to heterogeneity in tissue oxygenation

Miguel O. Bernabeu, Jakub Köry, James A. Grogan, Bostjan Markelc, Albert Beardo Ricol, Mayeul d’Avezac, Jakob Kaeppler, Nicholas Daly, James Hetherington, Timm Krüger, Philip K. Maini, Joe M. Pitt-Francis, Ruth J. Muschel, Tomás Alarcón, Helen M. Byrne
doi: https://doi.org/10.1101/640060
Miguel O. Bernabeu
Centre for Medical Informatics, Usher Institute, The University of Edinburgh, Edinburgh, UK
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  • For correspondence: miguel.bernabeu@ed.ac.uk helen.byrne@maths.ox.ac.uk
Jakub Köry
Mathematical Institute, University of Oxford, Oxford, UK
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James A. Grogan
Mathematical Institute, University of Oxford, Oxford, UK
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Bostjan Markelc
Department of Oncology, University of Oxford, Oxford, UKDepartment of Experimental Oncology, Institute of Oncology, Ljubljana, Slovenia
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Albert Beardo Ricol
Centre for Medical Informatics, Usher Institute, The University of Edinburgh, Edinburgh, UK
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Mayeul d’Avezac
Research Software Development Group, Research IT Services, University College London, London, UK
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Jakob Kaeppler
Department of Oncology, University of Oxford, Oxford, UK
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Nicholas Daly
Centre for Medical Informatics, Usher Institute, The University of Edinburgh, Edinburgh, UK
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James Hetherington
The Alan Turing Institute, London, UKDepartment of Computer Science, University College London, London, UK
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Timm Krüger
School of Engineering, Institute for Multiscale Thermofluids, The University of Edinburgh, Edinburgh, UK
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Philip K. Maini
Mathematical Institute, University of Oxford, Oxford, UK
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Joe M. Pitt-Francis
Department of Computer Science, University of Oxford, Oxford, UK
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Ruth J. Muschel
Department of Oncology, University of Oxford, Oxford, UK
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Tomás Alarcón
Centre de Recerca Matemàtica, Barcelona, Spain
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Helen M. Byrne
Mathematical Institute, University of Oxford, Oxford, UK
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  • For correspondence: miguel.bernabeu@ed.ac.uk helen.byrne@maths.ox.ac.uk
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Abstract

Heterogeneity in oxygen distribution in solid tumours is recognised as a limiting factor for therapeutic efficacy. Vessel normalisation strategies, aimed at rescuing abnormal tumour vascular phenotypes and alleviating hypoxia, have become an established therapeutic strategy. However, understanding of how pathological blood vessel networks and oxygen transport are related remains limited. In this paper, we establish a causal relationship between the abnormal vasculature of tumours and their heterogeneous tissue oxygenation. We obtain average vessel lengths Embedded Image and diameters Embedded Image from tumour allografts of three cancer cell lines and observe a substantial reduction in the ratio Embedded Image compared to physiological conditions. Mathematical modelling reveals that small values of the measured ratio λ (i.e. λ < 6) can bias haematocrit distribution in tumour vascular networks and drive highly heterogeneous tumour tissue oxygenation. Finally, we show an increase in the average λ value of tumour vascular networks following treatment with the DC101 anti-angiogenic cancer agent. Based on our findings, we propose a new oxygen normalisation mechanism associated with an increase in λ following treatment with antiangiogenic drugs.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted May 16, 2019.
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Abnormal morphology biases haematocrit distribution in tumour vasculature and contributes to heterogeneity in tissue oxygenation
Miguel O. Bernabeu, Jakub Köry, James A. Grogan, Bostjan Markelc, Albert Beardo Ricol, Mayeul d’Avezac, Jakob Kaeppler, Nicholas Daly, James Hetherington, Timm Krüger, Philip K. Maini, Joe M. Pitt-Francis, Ruth J. Muschel, Tomás Alarcón, Helen M. Byrne
bioRxiv 640060; doi: https://doi.org/10.1101/640060
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Abnormal morphology biases haematocrit distribution in tumour vasculature and contributes to heterogeneity in tissue oxygenation
Miguel O. Bernabeu, Jakub Köry, James A. Grogan, Bostjan Markelc, Albert Beardo Ricol, Mayeul d’Avezac, Jakob Kaeppler, Nicholas Daly, James Hetherington, Timm Krüger, Philip K. Maini, Joe M. Pitt-Francis, Ruth J. Muschel, Tomás Alarcón, Helen M. Byrne
bioRxiv 640060; doi: https://doi.org/10.1101/640060

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