Flow-based remodeling and function of tumor vasculature

描述（由申请人提供）：肿瘤血管的“正常化”已显示出改善化疗药物疗效的前景。理论上，靶向内皮VEGF信号传导的抗血管生成药物可以改善血管网络结构和功能，增强后续细胞毒性药物向癌细胞的转运。在实践中，效果是不可预测的，成功的程度也各不相同。抗VEGF疗法的主要作用是降低血管渗漏（导水率）、降低血管直径和修剪未成熟血管网络。据认为，这些因素中的每一个都可以影响血管网络的灌注，在以前缓慢或停滞的区域中诱导流动。不幸的是，当抗VEGF治疗影响血管结构和功能时，变化是动态的并且在时间上重叠，并且难以识别一致且可预测的正常化“窗口”，在该窗口期间灌注和随后的药物递送是最佳的。这在很大程度上是由于系统中的非线性，以及在临床试验或动物研究中无法区分血管泄漏减少的影响与网络结构变化的影响。我们已经开发了一个数学模型来计算由双光子显微镜成像的复杂肿瘤网络中的血流。该模型包含了解决肿瘤血管系统正常化问题的必要和充分的组成部分：i）脉管系统内和组织内的全流场的格子-玻尔兹曼计算，ii）可溶性物质如氧或药物在血管和组织域内的扩散和对流，iii）每种物质的不同的和空间分辨的血管水力传导率和渗透率，iv）红细胞颗粒在流中平流并以真实的氧释放动力学输送氧，v）剪切应力介导的血管重塑。我们建议使用该模型，指导下的多参数活体成像的肿瘤血管结构和功能，以确定肿瘤血管正常化的结构和功能的决定因素。 公共卫生相关性：肿瘤血管是长期不成熟和不稳定的，但抗血管生成药物可以诱导其形态发生的过程中，类似于适应性重塑伤口愈合。不幸的是，人们对由此产生的结构和功能变化如何影响氧气或药物向肿瘤的输送知之甚少。我们将应用一个数学模型来确定血管泄漏和网络结构的变化如何单独影响整个肿瘤的氧气和药物输送。

DESCRIPTION (provided by applicant): "Normalization" of tumor blood vessels has shown promise to improve the efficacy of chemotherapeutics. In theory, anti-angiogenic drugs targeting endothelial VEGF signaling can improve vessel network structure and function, enhancing the transport of subsequent cytotoxic drugs to cancer cells. In practice, the effects are unpredictable, with varying levels of success. The predominant effects of anti-VEGF therapies are decreased vessel leakiness (hydraulic conductivity), decreased vessel diameters and pruning of the immature vessel network. It is thought that each of these can influence perfusion of the vessel network, inducing flow in regions that were previously sluggish or stagnant. Unfortunately, when anti-VEGF therapies affect vessel structure and function, the changes are dynamic and overlapping in time, and it has been difficult to identify a consistent and predictable normalization "window" during which perfusion and subsequent drug delivery is optimal. This is largely due to the non-linearity in the system, and the inability to distinguish the effects of decreased vessel leakiness from those due to network structural changes in clinical trials or animal studies. We have developed a mathematical model to calculate blood flow in complex tumor networks imaged by two- photon microscopy. The model incorporates the necessary and sufficient components for addressing the problem of normalization of tumor vasculature: i) lattice-Boltzmann calculations of the full flow field within the vasculature and within the tissue, ii) diffusion and convection of soluble species such as oxygen or drugs within vessels and the tissue domain, iii) distinct and spatially-resolved vessel hydraulic conductivities and permeabilities for each species, iv) erythrocyte particles advecting in the flow and delivering oxygen with real oxygen release kinetics, v) shear stress-mediated vascular remodeling. We propose to use this model, guided by multi-parameter intravital imaging of tumor vessel structure and function, to determine the structural and functional determinants of tumor vessel normalization. PUBLIC HEALTH RELEVANCE: Tumor blood vessels are chronically immature and unstable, but anti-angiogenic drugs can induce their morphogenesis in a process resembling adaptive remodeling in wound healing. Unfortunately little is known about how the resulting structural and functional changes affects the delivery of oxygen or drugs to the tumor. We will apply a mathematical model to determine how changes in vessel leakiness and network structure individually influence oxygen and drug delivery throughout tumor.