Mechanical Regulation of Tumor Angiogenesis

肿瘤血管生成的机械调节

• 批准号: 9471682
• 负责人: Cynthia A. Reinhart-King
• 金额: $ 54.81万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9471682
• 关键词: Affect; Area; Attention; Biological Assay; Blood Circulation; Blood Vessels; Cell-Cell Adhesion; Cells; Chemicals; Collagen; Cues; Data; Drug Delivery Systems; Endothelial Cells; Exhibits; Gene Expression Regulation; Goals; Growth; Heterogeneity; Hypoxia; Imaging Techniques; Impairment; In Vitro; Mammary Neoplasms; Measures; Mechanics; Mediating; Metastatic breast cancer; Microvascular Permeability; Neoplasm Metastasis; Normal tissue morphology; PTK2 gene; Pathway interactions; Perfusion; Permeability; Phenotype; Physical environment; Play; Publishing; Radiation therapy; Regulation; Research Personnel; Role; Signal Transduction; Solid Neoplasm; Structure; Therapeutic; Tissues; Translational Research; Tumor Angiogenesis; Tumor Tissue; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vascularization; Work; angiogenesis; cancer therapy; cancer type; crosslink; density; differential expression; improved; in vitro Model; in vivo; in vivo Model; in vivo imaging; mechanical properties; migration; monolayer; new therapeutic target; novel; prevent; public health relevance; response; rho; success; synergism; transcriptome sequencing; translational medicine; tumor; tumor growth; tumor microenvironment; tumor progression

 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.

 描述（由申请人提供）：实体瘤中血管生成上调，但形成的微脉管系统比典型的脉管系统更曲折且更具渗透性。传统的癌症疗法集中于抑制血管生成以饥饿肿瘤。具有有害的影响，因为最小化血管生成会增加肿瘤的缺氧，这与化疗和放疗的功效降低有关。此外，不完整或渗漏的血管会促进内渗。因此，稳定脉管系统可能是一种有前途的治疗方法，可以最大限度地减少转移、提高化疗效果并改善肿瘤的药物输送，因为众所周知，VEGF 发挥着关键作用。然而，抗 VEGF 疗法在包括转移性乳腺癌在内的几种癌症类型中取得的成功有限。硬度，模仿乳腺肿瘤进展过程中发生的硬化，导致血管生成和内皮单层通透性增加——值得注意的是，这些内皮表型主要归因于 VEGF 的作用。此外，这些数据表明基质硬度。 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，该项目将研究基质硬化通过破坏内皮细胞-细胞粘附而导致肿瘤中微血管完整性受损的假设。 ，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。这里，3D 体外。 基质刚度模型、肿瘤硬化体内模型、先进的体内成像技术和 RNA-seq 将用于研究基质刚度改变肿瘤微环境中微血管通透性的机制。在目标 1 中，基质刚度和肿瘤硬化之间的协同作用。在目标 2 中，将定义 VEGF 介导的通透性。在目标 3 中，将研究抑制刚度诱导的方法。血管屏障破坏将会 共同探索，这项工作将导致确定新的治疗靶点，以使肿瘤血管系统正常化。