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

Research output: Contribution to journalArticle

  • Miguel O Bernabeu
  • Jakub Köry
  • James A Grogan
  • Bostjan Markelc
  • Albert Beardo
  • Mayeul d'Avezac
  • Romain Enjalbert
  • Jakob Kaeppler
  • Nicholas Daly
  • James Hetherington
  • Timm Krüger
  • Philip K Maini
  • Joe M Pitt-Francis
  • Ruth J Muschel
  • Tomás Alarcón
  • Helen M Byrne

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Original languageEnglish
Article number202007770
JournalProceedings of the National Academy of Sciences (PNAS)
Early online date27 Oct 2020
DOIs
Publication statusE-pub ahead of print - 27 Oct 2020

Abstract

Oxygen heterogeneity in solid tumours is recognised as a limiting factor for therapeutic efficacy. This heterogeneity arises from the abnormal vascular structure of the tumour, but the precise mechanisms linking abnormal structure and compromised oxygen transport are only partially understood. In this paper, we investigate the role that RBC transport plays in establishing oxygen heterogeneity in tumour 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 calculate 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 ratio λ (i.e. λ < 6) can bias haematocrit distribution in tumour vascular networks and drive heterogeneous oxygenation of tumour tissue. Finally, we show an increase in the value of λ in tumour vascular networks following treatment with the anti-angiogenic 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 tumour tissue undergoing anti-angiogenic treatment. Significance statement: Oxygen heterogeneity in solid tumours is recognised as a limiting factor for therapeutic efficacy. This heterogeneity arises from the abnormal tumour vascular structure. We investigate the role that anomalies in RBC transport play in establishing oxygen heterogeneity in tumour tissue. We introduce a metric to characterise tumour vasculature (mean vessel length-to-diameter ratio, λ) and demonstrate how it predicts tissue oxygen heterogeneity. We also report an increase in λ following treatment with the antiangiogenic agent DC101. Together, we propose λ as an effective way of monitoring the action of anti-angiogenic agents and a proxy measure of oxygen heterogeneity in tumour tissue. Unravelling the causal relationship between tumour vascular structure and tissue oxygenation will pave the way for new personalised therapeutic approaches.

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