Flow-based remodeling and function of tumor vasculature

描述（由申请人提供）：肿瘤血管的“正常化”已显示出提高化疗疗效的希望。理论上，靶向内皮细胞VEGF信号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，有不同程度的成功。抗vegf治疗的主要作用是减少血管渗漏（水力传导），减少血管直径和修剪未成熟的血管网络。据认为，这些都可以影响血管网络的灌注，在以前缓慢或停滞的区域诱导血流。不幸的是，当抗vegf治疗影响血管结构和功能时，这些变化是动态的，并且在时间上是重叠的，很难确定一个一致的和可预测的正常化“窗口”，在此期间灌注和随后的给药是最佳的。这主要是由于系统的非线性，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在复杂的肿瘤网络成像的双光子显微镜的血流量。该模型包含了解决肿瘤血管正常化问题的必要和充分的组成部分：i)血管和组织内的完整流场的晶格-玻尔兹曼计算，ii)血管和组织域内氧气或药物等可溶性物质的扩散和对流，iii)不同的和空间分辨的每种物质的血管导电性和渗透性，iv)红细胞颗粒在流动中平流并以真实的氧气释放动力学传递氧气，v)剪切应力介导的血管重塑。我们建议使用该模型，以肿瘤血管结构和功能的多参数活体成像为指导，确定肿瘤血管正常化的结构和功能决定因素。

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.