Impact of soluble and physical stimuli on tumor angiogenesis and drug sensitivity

可溶性和物理刺激对肿瘤血管生成和药物敏感性的影响

基本信息

批准号：
9015927
负责人：
Pamela K Kreeger
金额：
$ 16.64万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2017-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9015927
关键词：
3-Dimensional Address Adverse effects Angiogenic Factor Architecture Blood Vessels Breast Cancer Treatment Cells Characteristics Clinical Data Clinical Trials Collagen Complex Computer Analysis Computer Simulation Disease Progression Endothelial Cells Engineering Environment Extracellular Matrix Foundations Growth In Vitro Link Measures Mechanics Methods Microfluidics Modeling Multivariate Analysis Patients Permeability Pharmaceutical Preparations Process Property Quality of life Reporting Risk Site Stimulus Surface System Testing Therapeutic Tissues Transgenic Mice Tumor Angiogenesis Validation Variant Vascular Endothelial Growth Factors Work angiogenesis antiangiogenesis therapy base blood vessel development cancer type cost density design drug sensitivity in vitro Model in vivo individual patient inhibitor/antagonist innovation macrophage malignant breast neoplasm mouse model neoplastic cell novel outcome forecast physical property public health relevance response targeted agent targeted treatment tissue biomarkers treatment strategy tumor tumor growth tumor microenvironment tumor progression

项目摘要

DESCRIPTION (provided by applicant): Tumors must be able to induce angiogenesis in order to develop. Based on this mechanism, vascular-targeted therapies have been investigated in a variety of tumor types, with mixed results in clinical trials. Given the potential risks associated with these therapies, it is desirable to determine the characteristics of tissues (and hence, patients) that are most likely to respond to current inhibitors and identify additional therapeutic strategies. Angiogenesis occurs in a complex environment where endothelial cells are exposed to a variety of factors that are known to regulate angiogenesis, such as mechanical stiffness, extracellular matrix (ECM) density, and soluble growth factors. We hypothesize that the physical properties of the tumor microenvironment (e.g., stiffness, ECM density) impact tumor sensitivity to pro-angiogenic molecules, and therefore tumor responsiveness to vascular-targeted therapies. Aim 1: Evaluate how microenvironment properties impact endothelial cell (EC) responsiveness to soluble angiogenic stimuli. We will characterize the tumor microenvironment in a mouse model of breast cancer and apply this information to design a novel microfluidic-based culture system that enables independent variation of matrix stiffness and density. This system will be used to assess how different combinations of these characteristics impact cellular sensitivity to complex combinations of soluble angiogenic stimuli. We will then utilize computational modeling to analyze our experimental results in order to determine which angiogenic factors most strongly induce angiogenesis in the different physical microenvironments. Aim 2: Utilize tumor microenvironment properties and soluble factor combinations to predict EC responsiveness to vascular-targeted therapies. Using both our Aim 1 in vitro model and an in vivo mouse model of breast cancer, we will investigate whether the experimental and computational results gained in Aim 1 can be used to inform the selection of an optimal vascular-targeted strategies for a set microenvironment. By examining how the microenvironment regulates cellular sensitivity to angiogenic stimuli, this work aims to provide a foundation for predicting tumor responsiveness to vascular-targeted agents. The results obtained from these studies have the potential to inform the identification of treatment options for breast cancer.

描述（由适用提供）：肿瘤必须能够诱导血管生成才能发育。基于这种机制，已经研究了各种肿瘤类型的血管靶向疗法，在临床试验中结果混合。鉴于与这些疗法相关的潜在风险，希望确定最有可能应对当前抑制剂并确定其他治疗策略的组织（因此患者）的特征。血管生成发生在复杂的环境中，其中内皮细胞暴露于已知会调节血管生成的各种因素，例如机械刚度，细胞外基质（ECM）密度和固体生长因子。我们假设肿瘤微环境的物理特性（例如刚度，ECM密度）会影响肿瘤对促血管生成分子的敏感性，从而影响肿瘤对血管靶向疗法的反应。目标1：评估微环境特性如何影响内皮细胞（EC）对固体血管生成刺激的反应。我们将在乳腺癌的小鼠模型中表征肿瘤微环境，并将这些信息应用于设计一种新型的基于微流体的培养系统，该系统可以独立变化基质刚度和密度。该系统将用于评估这些特征的不同组合如何影响细胞对可溶性血管生成刺激的复杂组合的敏感性。然后，我们将利用计算模型来分析我们的实验结果，以确定哪些血管生成因子最强烈诱导不同物理微环境中的血管生成。目标2：利用肿瘤微环境和实心因子组合来预测EC对血管靶向疗法的反应。使用我们的AIM 1体外模型和乳腺癌的体内小鼠模型，我们将研究AIM 1中获得的实验和计算结果是否可用于为固定微环境的最佳血管靶向策略提供选择。通过检查微环境如何调节对血管生成刺激的细胞敏感性，该工作旨在为预测肿瘤对血管靶向剂的反应性提供基础。从这些研究中获得的结果有可能告知鉴定乳腺癌的治疗选择。