Physicochemical Cues and Their Roles in the Angiogenic Switch

血管生成开关在肿瘤血管形成和转移中起着重要作用[1];然而，微环境条件调节这一过程的潜在细胞和分子机制仍不清楚[2]。该项目将解决这样的假设，即不同的肿瘤样小生境的产生和位于这些小生境内的细胞之间的串扰上调了关键肿瘤细胞因子的表达，这些细胞因子有助于骨髓元素的募集和增强肿瘤血管生成。为了解决我们的假设，我们将利用基于物理科学的癌症生物学方法，该方法结合了3D细胞培养，微流体和数学建模。我们的研究设计基于4个目标：在目标1中，我们将设计3D 微流控肿瘤培养，这将使我们能够测试的假设，即信号的可溶性因子，调节空间分辨差异的氧张力和代谢变化，提供了旁分泌机制，跨越之间的小生境，以调节细胞因子的差异表达的肿瘤和基质细胞。在目标2中，我们将评估肿瘤和间质细胞的整体和局部动力学是否 如目标1所阐明的，信号传导影响侵袭性血管生成。为此，我们将扩展aim 1中开发的微流控平台，以整合血管化微通道。该系统将是可重塑的，并且可以进行调整以表现出增强的基质硬度，这是肿瘤基质的典型特征。在目标3中，我们将确定目标2中定义的新血管形成中的物理化学介导的变化是否导致影响表型身份、空间和时间贡献的血管小生境的形成， 骨髓前体细胞的生物学功能及其在肿瘤血管生成和转移灶形成中的作用。最后，在目标4中，我们将对微流控和物理化学改变的微血管中的骨基质元素进行动态全局转录组和表观基因组分析。生成的数据将被纳入计算信号转导网络分析，以确定 可能负责血管生成开关中物理化学介导的变化的分子靶点。 我们提出的研究有可能通过提高我们对肿瘤血管生成开关的理解和确定可能参与这一过程的分子机制来改善目前的抗血管生成治疗策略，并提供治疗相关的靶点。

The angiogenic switch plays a fundamental role in tumor vascularization and metastasis[1]; however, the underlying cellular and molecular mechanisms by which microenvironmental conditions regulate this process are still unclear[2]. This project will address the hypothesis that the creation of distinct tumor-like niches and crosstalk between cells residing within these niches up-regulates expression of pivotal tumor cytokines that contribute to the recruitment of bone marrow elements and enhanced tumor angiogenesis. To address our hypothesis we will utilize a physical-sciences based cancer biology approach that combines 3-D cell culture, microfluidics, and mathematical modeling. Our study design is based on 4 aims: In aim 1, we will design 3-D microfluidic tumor cultures that will allow us to test the hypothesis that the signaling of soluble factors, as regulated by spatially resolved differences in oxygen tension and metabolic changes, provides a paracrine mechanism that spans between niches to regulate the differential expression of cytokines by both tumor and stromal cells. In aim 2, we will evaluate whether the global and local dynamics of tumor and stromal ceil signaling, as elucidated in aim 1, impact invasion angiogenesis. To this end, we will expand the microfluidic platfomi developed in aim 1 to integrate vascularized microchannels. This system will be remodelable and can be adjusted to exhibit enhanced matrix stiffness as typical of the tumor stroma. In aim 3, we will determine whether physicochemically mediated changes in neovessel formation as defined in aim 2 lead to the formation of vascular niches that impact the phenotypic identity, spatial and temporal contribution, and biological function of bone marrow-progenitors and their role in tumor angiogenesis and metastatic niche fomiation. Finally, in aim 4, we will conduct dynamic global transcriptome and epigenome analysis of bone mamow elements that have incorporated in the microfluidic and physicochemically altered microvessels. The generated data will be incorporated into computational signal transduction network analysis to identify molecular targets that may be responsible for physicochemically mediated changes in the angiogenic switch. Our proposed studies have the potential to improve current strategies of anti-angiogenic therapies by enhancing our understanding of the tumor angiogenic switch and identifying molecular mechanisms that may be involved in this process and provide therapeutically relevant targets.