Biomechanical Regulation of Angiogenesis during Tumor Progression

肿瘤进展过程中血管生成的生物力学调节

• 批准号: 9582642
• 负责人: Mary Kathryn Sewell-Loftin
• 金额: $ 9.1万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9582642
• 关键词: Address; Behavior; Biochemical; Biological Assay; Biomechanics; Blood Vessels; Breast Cancer Model; Cancer Model; Cells; Cellular biology; Complement; Cues; Development; Effectiveness; Endothelial Cells; Environment; Exhibits; Extracellular Matrix; Fibrin; Fibroblasts; Future; Gel; Goals; Gold; Grant; Growth; Growth Factor; In Vitro; Intercellular Fluid; Investigation; KDR gene; Malignant Neoplasms; Mechanics; Mechanoreceptors; Mediating; Mesenchymal; Metabolic; Microfluidic Microchips; Microfluidics; Modeling; Mus; Myofibroblast; Neoplasm Metastasis; Pathway interactions; Phase; Phenotype; Physiological; Population; Process; Property; Proteins; Regulation; Research; Research Personnel; Research Training; Resolution; Role; Series; Signal Transduction; Smooth Muscle Actin Staining Method; Study models; System; Techniques; Therapeutic; Time; Training; Training Technics; Tumor Promotion; Vascular Endothelial Growth Factors; Vascularization; Work; angiogenesis; anti-cancer therapeutic; anticancer treatment; blood vessel development; cancer cell; cancer therapy; cancer type; career development; cell behavior; design; flexibility; fluid flow; improved; in vitro Model; in vivo; in vivo Model; innovation; knock-down; mechanical properties; mechanotransduction; mouse model; neoplastic cell; novel; prevent; rho; spatiotemporal; targeted cancer therapy; treatment strategy; tumor; tumor growth; tumor microenvironment; tumor progression

Project Summary During cancer progression, angiogenesis is upregulated to supply the ever-increasing metabolic demands of the growing tumor. While targeting tumor-associated angiogenesis has been a therapeutic strategy for many years, these techniques demonstrate limited effectiveness in many cancer types. We believe this may be due to limited understanding of the biomechanical environment of the tumor. Recently cancer-associated fibroblasts (CAFs) have been shown to be key regulators of the peritumoral environment responsible for secreting several growth factors that control angiogenesis and metastasis. CAFs exhibit a myofibroblast-like phenotype, with increases in alpha-smooth muscle actin and Snail1. We hypothesized that CAF-generated increases in biomechanical strains enhance tip cell activation and drive angiogenesis in the tumor microenvironment. Our initial work has demonstrated that CAF biomechanical activity is directly related to the vascularization potential of these cells in in vitro models of vascular growth, and that inhibiting the mechanotransductive pathways in these cells abrogated their ability to support the formation of blood vessel networks. Continuing this research will further elucidate the roles of biomechanics during tumor progression as well as reveal potential targets for novel anti-cancer therapeutic strategies. During the K99 portion of the grant, we will (1) investigate the role of CAF biomechanics in an in vivo angiogenic mouse model and (2) optimize a microfluidic platform for angiogenesis studies that will allow for isolation and interrogation of biomechanical parameters. The proposed microtissue platform will be highly innovative in that it allows for independent control of several key biomechanical properties. Importantly, this phase of the grant will complement the PI’s career development by incorporating training in cancer cell biology analysis techniques as well as mouse models of cancer progression. During the R00 portion of the grant, we will investigate how endothelial cells respond to mechanical cues from CAFs utilizing the microtissue model previously developed. Finally we will investigate potential anti-cancer therapeutic strategies targeting CAF biomechanical promotion of tumor development in a mouse model of breast cancer. Ultimately this work has significant implications for not only understanding biomechanics of cancer progression but also the development of a unique in vitro microtissue model that will permit interrogation of biomechanics in a truly original manner. The training, techniques, and approaches developed during this grant should open several new avenues for future studies and will allow the PI to transition into a fully-independent investigator.

项目摘要 在癌症进展过程中，血管生成被上调，以满足不断增长的代谢需求 不断生长的肿瘤。虽然以肿瘤相关血管生成为靶点一直是许多人的治疗策略 多年来，这些技术在许多癌症类型中显示出有限的有效性。我们认为这可能是由于 对肿瘤的生物力学环境的了解有限。最近与癌症相关的 成纤维细胞(CAF)已被证明是肿瘤周围环境的关键调节因子，负责 分泌几种控制血管生成和转移的生长因子。CAF呈肌成纤维样细胞 表型，α-平滑肌肌动蛋白和Snail1增加。我们假设由CAF产生的 生物力学应变的增加增强了肿瘤中TIP细胞的激活并驱动了血管生成 微环境。我们的初步工作表明，CAF的生物力学活性与 在血管生长的体外模型中，这些细胞的血管形成潜力，以及抑制 这些细胞中的机械转导途径丧失了它们支持血管形成的能力 网络。继续这项研究将进一步阐明生物力学在肿瘤进展中的作用 并揭示了新的抗癌治疗策略的潜在靶点。在拨款的K99部分期间， 我们将(1)研究CAF在体内血管生成小鼠模型中的生物力学作用；(2)优化 用于血管生成研究的微流控平台，将允许分离和询问生物力学 参数。拟议的微组织平台将是高度创新的，因为它允许独立控制 几个关键的生物力学特性。重要的是，这一阶段的拨款将补充私人侦探的职业生涯 通过结合癌细胞生物学分析技术以及小鼠模型的培训进行开发 癌症进展。在拨款的R00部分，我们将调查内皮细胞如何应对 利用之前开发的微组织模型来自CAF的机械提示。最后我们会调查 以CAF生物力学促进肿瘤发展为靶点的潜在抗癌治疗策略 小鼠乳腺癌模型。归根结底，这项工作不仅对理解 癌症进展的生物力学，以及一种独特的体外微组织模型的开发，它将 允许以真正原创的方式审问生物力学。培训、技巧和方法 在这笔赠款期间开发的应该会为未来的研究开辟几个新的途径，并将使PI能够 转变为一名完全独立的调查员。