EMT (epithelial mesenchymal transition) regulators and the crosstalk between the hypoxic and vascular tumor niche

启动稳态反应和适应缺氧的能力代表了实体瘤生长的中心方面，关键由关键转录调节因子缺氧诱导转录因子（HIF）-1a和HIF-2a控制。因此，低PO 2可以通过激活HIF系统触发肿瘤细胞通过诱导血管生成（血管生成表型）或通过从缺氧区域迁移到氧合良好的宿主组织和器官（侵袭表型）来覆盖其氧和营养供应。预先存在的或新形成的血管作为迁移支架来支持肿瘤扩散。有趣的是，目前的抗血管生成疗法似乎被一种类似的转变所抵消，这种转变使肿瘤细胞不依赖于新血管的生长。我们认为，这种信号传导反应的质的变化（血管生成与侵入性）可能是由氧水平在分子水平上反映HIF蛋白量（中度与高度）。为了验证这一假设，我们将分析HIF-1a和/或HIF-2a的不同作用和贡献，以及它们的蛋白水平，通过过表达和siRNA介导的敲低调节胶质母细胞瘤中HIF-1a和HIF-2a蛋白水平，诱导血管生成和（或）迁移/侵袭的定性反应变化。

The ability to initiate homeostatic responses and adapt to hypoxia represents a central aspect in solid tumor growth, crucially governed by the key transcriptional regulators hypoxia inducible transcription factor (HIF)-1a and HIF-2a. Thus, a low PO2 may via activation of the HIF system trigger the tumor cell to cover its oxygen and nutrient supply by inducing angiogenesis (angiogenic phenotype) or by migrating away from hypoxic areas into the well oxygenated host tissue and organs (invasive phenotype). Preexisting or newly formed vessels serve as migration scaffolds to support tumor spread. Interestingly, current antiangiogenic therapies seem to be counteracted by a similar switch to a more invasive phenotype that renders tumor cells independent of new blood vessel growth. We propose that such a qualitative change in the signaling response (angiogenic vs. invasive) may be governed by oxygen levels being reflected at the molecular level by HIF protein quantities (moderate vs. high). To test this hypothesis, we will analyze the distinct role and contribution of HIF-1a and/or HIF-2a and, with regard to their protein levels, the qualitative response changes in the induction of angiogenesis and (or) migration/invasion by modulating HIF-1a and HIF-2a protein levels in glioblastomas by overexpression and siRNA mediated knock-down.