Functional Interactions between HIF-1 and ECM in Cancer

许多人类癌症含有缺氧区域，导致细胞死亡并建立癌细胞的选择。癌细胞适应低氧微环境是通过转录因子低氧诱导因子1（HIF-1）的活性。HIF-1还通过激活内皮祖细胞和细胞在肿瘤血管形成中起关键作用。项目1将研究HIF-1和细胞外基质（ECM）之间的功能相互作用，无论是在癌细胞和内皮祖细胞和细胞。这是一个独特 这一观点考虑了肿瘤微环境的一个方面（O2浓度）如何调节并与另一个方面（ECM的机械特性）相互作用以改变癌细胞表型。我们提出的生物物理、生物化学、生物学、计算和工程方法的联合利用将为转移机制提供新的见解。具体目标是： (1)确定ECM机械特性的改变是否会改变癌细胞的表型。(2)确定缺氧和/或HIF-1活性增加是否会诱导ECM机械特性的变化，进而改变癌细胞的表型。(3)确定ECM机械特性的改变是否调节HIF-1活性，从而导致癌细胞表型的改变。 (4)确定ECM机械特性的变化是否改变内皮祖细胞和细胞的表型。(5)确定HIF-1诱导的ECM机械特性的变化是否改变内皮祖细胞和细胞的表型。与PS-OC的联系：项目1的研究目标符合HIF-1和EMC在转移级联中的合作作用中心的总体主题;目标1和2与项目2中的目标1-4以及项目3中的目标1和2协同连接，以进一步研究HIF-1和EMC在转移级联中的作用。 中心的研究整合;所有参与该项目的学生和研究员都将参加中心的培训计划;该项目将利用成像中心以及中心行政部门提供的资源;细胞系和微机械方法将与所有项目中使用的方法相同;计算工作将在所有项目中共享。

Many human cancers contain regions of hypoxia, resulting in cell death and establishing a selection for cancer cells. Cancer cells adapt to the hypoxic microenvironment is through the activity of the transcription factor hypoxia-inducible factor 1 (HIF-1). HIF-1 also plays a crifical role in tumor vascularization by activation of endothelial progenitors and cells. Project 1 will investigate the functional interactions between HIF-1 and extracellular matrix (ECM), both in cancer cells and in endothelial progenitors and cells. This is a unique perspective that takes into account how one aspect of the tumor microenvironment (02 concentration) regulates and interacts with another (mechanical properties of the ECM) to alter the cancer cell phenotype. The combined utilization of biophysical, biochemical, biological, computational, and engineering approaches that we propose will provide new insights into the mechanisms underiying metastasis. The Specific Aims are: (1) To determine whether alterations in mechanical properties of the ECM alter the phenotype of cancer cells.(2) To determine whether hypoxia and/or increased HIF-1 activity induces changes in mechanical properties of the ECM, which in turn alter the phenotype of cancer cells. (3) To determine whether alterations in mechanical properties of the ECM regulate HIF-1 activity, leading to alterations in cancer cell phenotype. (4) To determine whether changes in ECM mechanical properties alter the phenotype of endothelial progenitors and cells. (5) To determine whether HIF-1-induced changes in ECM mechanical properties alter the phenotype of endothelial progenitors and cells. Linkage to PS-OC: The research aims of Project 1 fit the overarching theme of the Center of the cooperative role of HIF-1 and EMC in the metastatic cascade; Aims 1 and 2 are synergistically connected to Aims 1-4 in Project 2 and Aims 1 and 2 in Project 3 for further research integrafion of the Center; all Students and Fellows in the Project will be enrolled in the Center Training Program; this project will make use of the resources provided by the Imaging Core, as well as the Administrative Unit of the Center; cell lines and micromechanical methods will be the same as those used in all projects; computational efforts will be shared among all projects.