Structural Adaptation and Heterogeneity of Normal and Tumor Microvascular Networks

Abstract

Relative to normal tissues, tumor microcirculation exhibits high structural and functional heterogeneity leading to hypoxic regions and impairing treatment efficacy. Here, computational simulations of blood vessel structural adaptation are used to explore the hypothesis that abnormal adaptive responses to local hemodynamic and metabolic stimuli contribute to aberrant morphological and hemodynamic characteristics of tumor microcirculation. Topology, vascular diameter, length, and red blood cell velocity of normal mesenteric and tumor vascular networks were recorded by intravital microscopy. Computational models were used to estimate hemodynamics and oxygen distribution and to simulate vascular diameter adaptation in response to hemodynamic, metabolic and conducted stimuli. The assumed sensitivity to hemodynamic and conducted signals, the vascular growth tendency, and the random variability of vascular responses were altered to simulate ‘normal’ and ‘tumor’ adaptation modes. The heterogeneous properties of vascular networks were characterized by diameter mismatch at vascular branch points (d3 var) and deficit of oxygen delivery relative to demand (O2def). In the tumor, d3 var and O2def were higher (0.404 and 0.182) than in normal networks (0.278 and 0.099). Simulated remodeling of the tumor network with ‘normal’ parameters gave low values (0.288 and 0.099). Conversely, normal networks attained tumor-like characteristics (0.41 and 0.179) upon adaptation with ‘tumor’ parameters, including low conducted sensitivity, increased growth tendency, and elevated random biological variability. It is concluded that the deviant properties of tumor microcirculation may result largely from defective structural adaptation, including strongly reduced responses to conducted stimuli.

RNAi-mediated gene knockdown and anti-angiogenic therapy of RCCs using a cyclic RGD-modified liposomal-siRNA system

“…As the tumor vasculature is more heterogenous than normal tissue, blood flow is not sufficient in some parts of tumor vessels [36,37]. This heterogeneity in blood flow could lead to a limited distribution of the systemically delivered RGD-MEND.…”

The Relationship between Tumor Blood Flow, Angiogenesis, Tumor Hypoxia, and Aerobic Glycolysis

“…The tendency of the tumor microcirculation to lose normal hemodynamic control has been described and modeled in detail by Pries and colleagues (17,18), who also coined the associated "shunt problem": poor extraction of oxygen, glucose, and pharmaceuticals in tumors as blood is effectively shunted through capillaries with poorly controlled flow (18). The extent to which the extraction of diffusible substances is reduced by the loss of normal hemodynamic control across the capillary bed can be addressed by advanced simulation models of the microcirculation (17,18).…”

“…This notion is difficult to reconcile with the finding that tumor oxygenation in many cases improves as a result of antiangiogenic treatment, during which average intercapillary distances invariably increase. A more recent hypothesis of chronic tumor hypoxia posits that the microvasculature tends to develop functional arteriovenous shunts in the absence of the normal signaling of metabolic needs among microvessels (17). If vascular normalization restored normal signaling, such shunting might be reduced, the distribution of blood across the microvasculature improved, and oxygen extraction thereby increased (18).…”

Tumor microenvironment: a mechanical force link

“…Structurally, tumor blood vessels are tortuous and dilated, and they are distributed very heterogeneously with many areas lacking vasculature [4]. Moreover, tumor blood vessels lack adequate pericytes coverings.…”