Flow-based remodeling and function of tumor vasculature

描述(申请人提供)：肿瘤血管的“正常化”已显示出改善化疗疗效的希望。理论上，以血管内皮生长因子信号转导为靶点的抗血管生成药物可以改善血管网络结构和功能，增强后续细胞毒药物向癌细胞的转运。在实践中，影响是不可预测的，成功的程度各不相同。抗血管内皮生长因子治疗的主要效果是减少血管渗漏(水力传导性)，减少血管直径和修剪未成熟的血管网络。据认为，这些因素中的每一个都可以影响血管网络的血流，在以前缓慢或停滞的区域诱导血流。不幸的是，当抗血管内皮生长因子治疗影响血管结构和功能时，这种变化在时间上是动态的和重叠的，很难确定一个一致的和可预测的正常化窗口，在此期间灌流和随后的药物输送是最佳的。这在很大程度上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渗漏减少的影响和网络结构变化造成的影响。我们开发了一个数学模型来计算通过双光子显微镜成像的复杂肿瘤网络中的血流量。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件：i)格子-Boltzmann计算血管内和组织内的全部流场，ii)血管和组织区域内氧或药物等可溶性物质的扩散和对流，iii)每个物种独特的和空间分辨的血管水力传导性和通透性，iv)红细胞颗粒在流动中平流并以真实的氧气释放动力学输送氧气，v)剪应力介导的血管重建。我们建议使用这个模型，在肿瘤血管结构和功能的多参数活体成像的指导下，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.