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

 描述（由申请人提供）：肿瘤必须能够诱导血管生成才能发展。基于这一机制，血管靶向治疗已在多种肿瘤类型中进行了研究，临床试验结果喜忧参半。考虑到与这些治疗相关的潜在风险，需要确定最有可能对当前抑制剂产生反应的组织（以及因此患者）的特征，并确定其他治疗策略。血管生成发生在复杂的环境中，其中内皮细胞暴露于已知调节血管生成的多种因子，例如机械刚度、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性质（例如，硬度、ECM密度）影响肿瘤对促血管生成分子敏感性，并因此影响肿瘤对血管靶向治疗的反应性。目的1：评价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性。我们将描述乳腺癌小鼠模型中的肿瘤微环境，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，该系统能够独立改变基质的硬度和密度。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，我们将利用计算建模来分析我们的实验结果，以确定哪些血管生成因子在不同的物理微环境中最强烈地诱导血管生成。目的2：利用肿瘤微环境特性和可溶性因子组合预测EC对血管靶向治疗的反应性。使用我们的目标1体外模型和乳腺癌的体内小鼠模型，我们将研究目标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性提供基础。从这些研究中获得的结果有可能为乳腺癌治疗方案的确定提供信息。

 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.