Modelling the transport of fluid through heterogeneous, whole tumours in silico

Abstract

AbstractIt is critically important to understand and predict fluid transport within both physiological and pathological tissues in order to develop effective treatment strategies. Recent advances in high-resolution optical imaging allow the acquisition of whole tumour vascular networks which can be used to parameterise computational models to predict the fluid dynamics at all length scales across the tissue. This enables hypothesis testing around the role of the tumour microenvironment in determining transport characteristics, which would otherwise be unavailable using traditional experiments.In this study, we present a novel computational framework for the efficient simulation of vascular blood flow and interstitial fluid transport based on complete three-dimensional, whole tumour vasculature obtained using high-resolution optical imaging. This framework comprises a Poiseuille flow model which simulates vascular blood flow within the vessel network, coupled via point sources of flux to a porous medium model describing interstitial fluid transport. We develop a computational algorithm for prescription of network boundary conditions and validation of tissue-scale fluid transport against measured in vivo perfusion data acquired using biomedical imaging tools. We present simulations of the model on orthoptic murine glioma and human colorectal carcinoma xenograft data (GL261 and LS147T, respectively), and perform sensitivity analysis on key unknown parameters relating to the tissue microenvironment, to understand their impact in predicting vascular and interstitial flow. Finally, we simulate radially varying vascular normalisation in a LS147T tumour and hypothesise that uniform normalisation is required to lower tumour interstitial fluid pressure.Our computational framework permits predictions of whole tumour fluid dynamics which incorporate the inherent architectural heterogeneities appearing at the micron-scale, and outputs three-dimensional spatial maps detailing these flow properties from micro to macro length scales. This provides vital information on the tumour microenvironment which could enable the design and delivery of future anti-cancer therapies.Author summaryThe structure of tumours varies widely, with dense and chaotically-formed networks of blood vessels that differ between each individual tumour and even between different regions of the same tumour. This atypical environment can inhibit the delivery of anti-cancer therapies. Computational tools are urgently required which incorporate micron-scale tumour biomechanics to predict tissue-scale fluid dynamics, and consequently the efficacy of cancer therapies.We have developed a computational framework which integrates the complex tumour vascular architecture to predict fluid transport across all lengths scales in whole tumours. This enables computationally efficient hypothesis testing of cancer therapies which manipulate the tumour microenvironment in order to improve drug delivery to tumours.