Molecular oxygen sensing and PHD-inhibition: implications for colorectal cancer growth

分子氧传感和 PHD 抑制：对结直肠癌生长的影响

• 批准号: 142603777
• 负责人: Professor Dr. Martin A. Schneider
• 金额: --
• 依托单位: Klinik für Allgemein-, Viszeral- und Transplantationschirurgie
• 依托单位国家: 德国
• 项目类别: Clinical Research Units
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/142603777?language=en
• 关键词: Molecular; oxygen; sensing; PHD; inhibition

Hypoxia-inducible factors (HIFs) are transcriptional master regulators in the adaptive response to oxygen deprivation (hypoxia), and affect cancer growth by altering the expression of numerous target genes involved in tumor cell survival, proliferation, metabolism, angiogenesis and metastasis. HIF prolyl hydroxylase enzymes (PHD1, PHD2 and PHD3) are molecular oxygen sensors regulating the activity of HIFs. Since these PHD enzymes can be inhibited applying pharmacological inhibitors, they are potential therapeutic targets. Specifically, current insight suggests that PHD-inhibition may improve liver function following major hepatectomy, which represents a cornerstone in the clinical management of colorectal liver metastases. Data obtained during the first funding period revealed that expression of PHD3 (but not of PHD1 or PHD2) is down-regulated in human colorectal cancer specimens compared to healthy gut mucosa, and that low tumor-expression of PHD3 correlates with increased frequency of distant metastases. Consistently, functional genetic analyses revealed that over-expression of PHD3 in colorectal cancer cells attenuates tumor growth and metastasis in various mouse colon tumor models. Independently from its function in the cancer cells themselves, PHD3 was expressed in stromal macrophages of human colorectal cancer tissues. Indeed, genetic loss of function studies revealed that loss of PHD3 specifically induces the maturation and pro-inflammatory activation of macrophages. Taken together, these findings suggest that loss of PHD3-expression in tumor cells exerts tumor-suppressive effects, whereas its expression in innate immune cells may independently regulate proinflammatory and tumor-suppressive effects of tumor-associated macrophages. In the second funding period, we propose to further elucidate the suspected dual functions for PHD3 in colon cancer cells and tumor-associated macrophages, and their coordinate effects on colorectal cancer progression. Furthermore, in order to assess how these insights translate to potential applications of pharmacologic PHD-inhibition in colorectal cancer patients, we will assess the effects of pharmacologic PHD-inhibition on the expansion of colorectal liver metastases, particularly in the setting of surgical liver resection.

低氧诱导因子(HIF)是对缺氧的适应性反应的转录调控因子，通过改变肿瘤细胞存活、增殖、代谢、血管生成和转移等多种靶基因的表达来影响肿瘤的生长。HIF Pro羟基酶(PhD1、PHD2和PHD3)是调节HIF活性的分子氧感受器。由于这些PHD酶可以被药物抑制剂抑制，因此它们是潜在的治疗靶点。具体地说，目前的研究表明，抑制PHD可以改善大范围肝切除术后的肝功能，这是临床治疗结直肠癌肝转移的基石。在第一个资助期内获得的数据显示，与健康的肠道粘膜相比，PHD3的表达在人类结直肠癌标本中下调，并且PHD3的低表达与远处转移的频率增加有关。功能遗传学分析一致地表明，在不同的小鼠结肠肿瘤模型中，PHD3在结直肠癌细胞中的过度表达可以减少肿瘤的生长和转移。与其在癌细胞中的功能无关，PHD3在人结直肠癌组织的间质巨噬细胞中表达。事实上，遗传功能丧失研究表明，PHD3的缺失特异性地诱导巨噬细胞的成熟和促炎激活。综上所述，这些发现表明，肿瘤细胞中PHD3-表达的缺失发挥了肿瘤抑制作用，而其在天然免疫细胞中的表达可能独立地调节肿瘤相关巨噬细胞的促炎和肿瘤抑制作用。在第二个资助期，我们建议进一步阐明PHD3在结肠癌细胞和肿瘤相关巨噬细胞中可能具有的双重功能，以及它们在结直肠癌进展中的协同作用。此外，为了评估这些见解如何转化为药理学PHD抑制在结直肠癌患者中的潜在应用，我们将评估药理学PHD抑制对结直肠癌肝转移扩大的影响，特别是在外科肝切除的背景下。