Knaup Karl X, Guenther Regina, Stoeckert Johanna, Monti Juliana M, Eckardt Kai-Uwe, Wiesener Michael S
Department of Nephrology and Hypertension, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany.
J Cancer. 2017 Jul 1;8(10):1809-1817. doi: 10.7150/jca.16486. eCollection 2017.
The Hypoxia Inducible Transcription Factor (HIF) is the master regulator of cellular response to hypoxic adaptation. Solid tumors inevitably harbour hypoxic regions with subsequent stabilization and activation of HIF and HIF target genes due to poor vascularization and rapid growth. The mammalian target of rapamycin (mTOR) is a global regulator of cellular growth and proliferation, which can also regulate HIF expression independantly of hypoxia via specific activation of cellular translation and transcription. An effective blockade of mTOR results in attenuation of HIF under hypoxic conditions . This mechanism could enable a simultaneous inhibition of both the mTOR- and the HIF-pathway, resulting in an effective tool for cancer targeting. We set out to analyze the effect of mTOR inhibition and the involvement of mTOR regulation on HIF in a subcutaneous xenograft model in nude mice. Our results demonstrate that mTOR inhibition in our model leads to a clear reduction in tumor growth of various cellular origins, most likely due to inhibition of cellular proliferation. Moreover, these effects can also be achieved independently of the HIF status of the tumor cells. The HIF levels seem to remain unaffected by mTOR inhibition, probably due to the profound hypoxic environment in these threedimensional structures, consequently leading to a strong HIF stabillization. Therefore, treatment of these experimental tumors with mTOR inhibitors is an effective tool to achieve size regression. The involvement of and the effect on HIF in this setting is nevertheless negligible.
缺氧诱导转录因子（HIF）是细胞对缺氧适应反应的主要调节因子。实体瘤不可避免地存在缺氧区域，由于血管生成不良和生长迅速，随后会出现HIF及其靶基因的稳定和激活。雷帕霉素哺乳动物靶点（mTOR）是细胞生长和增殖的全局调节因子，它还可以通过细胞翻译和转录的特异性激活，独立于缺氧调节HIF表达。有效阻断mTOR会导致缺氧条件下HIF减弱。这种机制可以同时抑制mTOR和HIF途径，从而成为一种有效的癌症靶向工具。我们着手分析在裸鼠皮下异种移植模型中mTOR抑制的效果以及mTOR调节对HIF的影响。我们的结果表明，在我们的模型中，mTOR抑制导致各种细胞来源的肿瘤生长明显减少，这很可能是由于细胞增殖受到抑制。此外，这些效果也可以独立于肿瘤细胞的HIF状态实现。HIF水平似乎不受mTOR抑制的影响，这可能是由于这些三维结构中存在严重的缺氧环境，从而导致HIF强烈稳定。因此，用mTOR抑制剂治疗这些实验性肿瘤是实现肿瘤大小缩小的有效工具。然而，在这种情况下，mTOR对HIF的影响可以忽略不计。
