Mechanical Regulation of Tumor Angiogenesis

 描述（由申请人提供）：血管生成在实体瘤中上调，但形成的微血管比典型的血管更曲折和更具渗透性。传统的癌症治疗集中在抑制血管生成以饿死肿瘤。然而，最近的证据表明，这种方法可能具有有害作用，因为最小化血管生成增加了肿瘤中的缺氧，这与化疗和放疗的疗效降低有关。此外，不完整或渗漏的血管可促进转移细胞向脉管系统的内渗。因此，稳定脉管系统可能是一种有前途的治疗方法，以最大限度地减少转移，增加化疗疗效和改善药物递送到肿瘤。已经将重点放在靶向VEGF上，因为已知其在促进血管生成和引起血管通透性增加中起关键作用。然而，抗VEGF疗法在几种癌症类型中取得了有限的成功，包括转移性乳腺癌。研究人员令人兴奋的新数据表明，基质硬度模仿乳腺肿瘤进展期间发生的硬化，导致血管生成生长增加和内皮单层通透性增加-值得注意的是，这些是主要归因于VEGF作用的相同内皮表型。此外，这些数据表明， 增强内皮细胞对VEGF的通透性反应，表明VEGF和基质硬度介导的信号传导之间存在串扰。鉴于这些发现，本项目将研究以下假设：基质硬化通过破坏内皮细胞-细胞粘附而导致肿瘤微血管完整性受损，相应地，抑制硬化和/或内皮细胞对硬化的反应可以最大限度地减少血管完整性受损。在这里，3D体外 基质硬度模型、肿瘤硬化体内模型、先进的体内成像技术和RNA-seq将用于研究基质硬度改变肿瘤微环境中微血管通透性的机制。在目标1中，将定义基质硬度和VEGF介导的渗透性之间的协同作用。在目标2中，将研究基质中的机械不均匀性对血管生长和完整性的影响。在目标3中，将介绍抑制僵硬诱导的血管屏障破坏的方法。 探讨了总之，这项工作将导致识别新的治疗靶点，使肿瘤血管系统正常化。

 DESCRIPTION (provided by applicant): Angiogenesis is upregulated in solid tumors, but the microvasculature that forms is more tortuous and permeable than typical vasculature. Traditional cancer therapies have focused on inhibiting angiogenesis to starve tumors. However, more recent evidence suggests that this approach may have deleterious effects because minimizing angiogenesis increases hypoxia in the tumor which is associated with decreased efficacy of chemotherapeutic and radiation treatment. Moreover, incomplete or leaky vessels can facilitate the intravasation of metastatic cells into the vasculature. As such, stabilizing vasculature may be a promising therapeutic approach to minimizing metastasis, increasing chemotherapeutic efficacy and improving drug delivery to the tumor. Significant emphasis has been placed on targeting VEGF, as it is known to play a key role in promoting angiogenesis and causing increased vascular permeability. However, anti-VEGF therapeutics has met with limited success in several cancer types, including metastatic breast cancer. The researchers' exciting, new data indicates that matrix stiffness, mimicking the stiffening that occurs during breast tumor progression, causes increased angiogenic outgrowth and increased endothelial monolayer permeability- notably, these are the same endothelial phenotypes that are attributed primarily to the action of VEGF. Moreover, these data indicate that matrix stiffness augments endothelial permeability response to VEGF, suggesting a crosstalk between VEGF and matrix stiffness-mediated signaling. Given these findings, this project will investigate the hypothesis that matrix stiffening contributes to impaired microvascular integrity in tumors by disrupting endothelial cell-cell adhesion, and correspondingly, inhibition of stiffening and/or endothelial cell response to stiffening can minimize impaired vascular integrity. Here, 3D in vitro models of matrix stiffness, in vivo models of tumor stiffening, advanced in vivo imaging techniques and RNA-seq will be used to investigate the mechanism by which matrix stiffness alters microvascular permeability in the tumor microenvironment. In Aim 1, the synergies between matrix stiffness and VEGF-mediated permeability will be defined. In Aim 2, the effects of mechanical heterogeneities in the matrix on vessel outgrowth and integrity will be investigated. In Aim 3, approaches to inhibit stiffness-induced vascular barrier disruption will be explored. Together, this work will lead to the identification of novel therapeutic targets to normalize tumor vasculature.