Abstract
We present a computational model for trans-vascular oxygen transport in synthetic tumor and host tissue blood vessel networks, aiming at qualitatively explaining published data of optical mammography, which were obtained from 87 breast cancer patients. The data generally show average hemoglobin concentration to be higher in tumors versus host tissue whereas average oxy-to total hemoglobin concentration (vascular segment RBC-volume-weighted blood oxygenation) can be above or below normal. Starting from a synthetic arterio-venous initial network the tumor vasculature was generated by processes involving cooption, angiogenesis, and vessel regression. Calculations of spatially resolved blood flow, hematocrit, oxy- and total hemoglobin concentrations, blood and tissue oxygenation were carried out for ninety tumor and associated normal vessel networks starting from various assumed geometries of feeding arteries and draining veins. Spatial heterogeneity in the extra-vascular partial oxygen pressure distribution can be related to various tumor compartments characterized by varying capillary densities and blood flow characteristics. The reported higher average hemoglobin concentration of tumors is explained by growth and dilatation of tumor blood vessels. Even assuming sixfold metabolic rate of oxygen consumption in tumorous versus host tissue, the predicted oxygen hemoglobin concentrations are above normal. Such tumors are likely associated with high tumor blood flow caused by high-caliber blood vessels crossing the tumor volume and hence oxygen supply exceeding oxygen demand. Tumor oxy- to total hemoglobin concentration below normal could only be achieved by reducing tumor vessel radii during growth by a randomly selected factor, simulating compression caused by intra-tumoral solid stress due to proliferation of cells and extracellular matrix. Since compression of blood vessels will impede chemotherapy we conclude that tumors with oxy- to total hemoglobin concentration below normal are less likely to respond to chemotherapy. Such behavior was recently reported for neo-adjuvant chemotherapy of locally advanced breast tumors.
Highlights
Adequate supply of tissue with oxygen and nutrients critically depends on the structure and function of its vasculature
Considerable data scatter in simulated quantities, e.g. tumor tissue hemoglobin concentration and tissue blood oxygenation are related to vascular variance of initial blood vessel networks and qualitatively explain the scatter of clinical data of the patient cohort
Breast tumors with tissue blood oxygenation above normal are likely associated with high tumor blood flow caused by high-caliber blood vessels penetrating into the tumor
Summary
Adequate supply of tissue with oxygen and nutrients critically depends on the structure and function of its vasculature. The vasculature of solid tumors, is known to differ distinctly from that of surrounding normal tissue. The structurally abnormal tumor vasculature results in spatially and temporally heterogeneous blood flow, affecting tissue oxygenation (acute or perfusion-limited hypoxia). From intravital dorsal window microscopy on tumor models it is known that blood flow through tumor capillaries is frequently sluggish and at times may even be stationary and reverse direction. It follows that blood flow through tumors may not follow a constant unidirectional path. Tissue solid pressure, generated by proliferating cancer cells and modifications of the extracellular matrix of tumors, may compress tumor blood vessels reducing or impairing blood flow [9,10,11]. Tumor hypoxia is associated with poor prognosis, because it causes resistance to standard therapies and promotes more aggressive phenotypes [12, 13]
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