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

 描述(申请人提供)：肿瘤必须能够诱导血管生成才能发展。基于这一机制，血管靶向治疗已在各种肿瘤类型中进行了研究，临床试验结果喜忧参半。考虑到与这些疗法相关的潜在风险，有必要确定最有可能对当前的抑制剂产生反应的组织(因此，患者)的特征，并确定其他治疗策略。血管生成发生在一个复杂的环境中，血管内皮细胞暴露在各种已知调节血管生成的因素中，如机械硬度、细胞外基质(ECM)密度和可溶性生长因子。我们假设肿瘤微环境的物理属性(如硬度、ECM密度)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治疗的反应。目的1：评估微环境特性如何影响内皮细胞(EC)对可溶性血管生成刺激的反应。我们将在乳腺癌的小鼠模型中描述肿瘤微环境的特征，并应用这些信息来设计一种新的基于微流控的培养系统，使基质硬度和密度能够独立变化。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，以确定在不同的物理微环境中，哪些血管生成因子最强地诱导血管生成。目的2：利用肿瘤微环境特性和可溶性因子组合来预测EC对血管靶向治疗的反应性。使用我们的Aim 1体外模型和体内小鼠乳腺癌模型，我们将调查在Aim 1中获得的实验和计算结果是否可以用于为设定的微环境选择最佳的血管靶向策略。通过研究微环境如何调节细胞对血管生成刺激的敏感性，这项工作旨在为预测肿瘤对血管靶向药物的反应提供基础。从这些研究中获得的结果有可能为确定乳腺癌的治疗方案提供信息。

 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.