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

Abstract

Oxygen heterogeneity 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 the potential to improve tumour responses to treatments such as radiotherapy and chemotherapy. However, understanding how pathological blood vessel networks and oxygen transport are related remains limited. In this paper, we propose a novel source of oxygen heterogeneity in tumour tissue associated with the abnormal transport of red blood cells. We calculate average vessel lengthsL and diametersd from tumour allografts of three cancer cell lines and observe a substantial reduction in the ratio λ =L/d 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 a mechanism for oxygen normalisation associated with an increase in λ following treatment with anti-angiogenic drugs.

Vessel compression biases red blood cell partitioning at bifurcations in a haematocrit-dependent manner: implications for tumour blood flow

“…However, our data suggest that up to 100D of length is required for an initially compacted RBC distribution to expand and reach a steady distribution when the haematocrit is 10%. This finding supports the view that the cross-sectional distribution of RBCs at low in vivo haematocrits may be away from equilibrium not only in diseased vascular networks, as we previously showed in tumours [14], but also under physiological conditions where inter-bifurcation lengths average fewer than 100D. Further research into the network-level dynamics arising from our results is warranted.…”

“…First, our results show that the effect of vessel compression on the downstream partitioning of RBCs is only apparent when discharge haematocrit and the distance between the compression and the bifurcation is sufficiently low. Another study by our group showed that two consecutive bifurcations within a short distance can also alter the partitioning of RBCs at the downstream bifurcation [14]. Furthermore, we showed that interbifurcation distances are much reduced in the tumour micro-environment, and Kamoun et al .…”

“…Oxygen binds to haemoglobin in red blood cells (RBCs) and is transported through the vasculature with the RBCs. We recently identified the reduced inter-bifurcation distance associated with the pro-angiogenic tumour environment as a source of oxygen heterogeneity via its impact on RBC splitting at bifurcations [14]. However, the impact that other tumour vascular phenotypes, such as vessel compression, play on this process is not known.…”

“…However, the abnormal TME is associated with marked heterogeneity in haematocrit [12], including reports of plasma-only channels [13]. We recently identified reduced inter-bifurcation distance as a source of haematocrit variation via its impact on RBC partitioning at bifurcations [14]. However, the impact that other tumour vascular phenotypes such as vessel compression play on this process is not known.…”

Association between erythrocyte dynamics and vessel remodelling in developmental vascular networks

“…Our group has recently identified reduced interbifurcation distance and complex branching topology as sources of haematocrit asymmetry in the context of tumour blood flow. Furthermore, we propose a role for the resulting abnormal partitioning in establishing tumour tissue hypoxia(58).…”