Mechanical Regulation of Tumor Angiogenesis

 描述(申请人提供)：血管生成在实体瘤中上调，但形成的微血管系统比典型的血管系统更曲折和易渗透。传统的癌症疗法一直专注于抑制血管生成，以饥饿肿瘤。然而，最近的证据表明，这种方法可能有有害的影响，因为最小化血管生成增加了肿瘤中的缺氧，这与化疗和放射治疗的疗效降低有关。此外，不完整或渗漏的血管可促进转移细胞进入血管系统。因此，稳定血管系统可能是一种很有前途的治疗方法，可以最大限度地减少转移，提高化疗效果，并改善对肿瘤的药物输送。靶向血管内皮细胞生长因子一直是研究的重点，因为众所周知，它在促进血管生成和增加血管通透性方面起关键作用。然而，抗血管内皮生长因子疗法在几种癌症类型上的成功有限，包括转移性乳腺癌。研究人员令人兴奋的新数据表明，基质僵硬模拟乳腺癌进展过程中发生的僵硬，导致血管新生生长增加和内皮单层通透性增加-值得注意的是，这些都是主要归因于血管内皮生长因子作用的相同的内皮表型。此外，这些数据表明，矩阵刚度 增强血管内皮细胞对血管内皮生长因子的通透性反应，提示血管内皮生长因子和基质刚性介导的信号转导之间存在串扰。鉴于这些发现，本项目将探讨这样的假设，即基质硬化通过破坏内皮细胞与细胞的黏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将受损的血管完整性降至最低。这是3D试管技术 将使用基质僵硬模型、肿瘤硬化的体内模型、先进的体内成像技术和RNA-SEQ来研究基质僵硬改变肿瘤微环境中微血管通透性的机制。在目标1中，将定义基质硬度和血管内皮生长因子介导的通透性之间的协同作用。在目标2中，将研究基质中的机械异质性对血管生长和完整性的影响。在目标3中，抑制僵硬诱导的血管屏障破坏的方法将是 探索过了。总之，这项工作将导致识别新的治疗靶点，以使肿瘤血管正常化。

 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.