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

基本信息

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

项目摘要

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.

缺氧诱导因子（HIF）是对氧剥夺（缺氧）的适应性反应中的转录主要调节剂，并通过改变参与肿瘤细胞存活，增殖，代谢，血管生成和转移的许多靶基因的表达来影响癌症的生长。 HIF羟基羟化酶（PHD1，PHD2和PHD3）是调节HIF活性的分子氧气传感器。由于这些博士学位酶可以抑制使用药理学抑制剂，因此它们是潜在的治疗靶标。具体而言，当前的见解表明，在重大肝切除术后，抑制博士学位可以改善肝功能，这代表了结直肠肝转移的临床管理中的基石。在第一个资金期间获得的数据表明，与健康的肠粘膜相比，人类大肠癌标本中PHD3（但不是PHD1或PHD2）的表达被下调，而PHD3的低肿瘤表达与远处转移频率的增加相关。一致地，功能性遗传分析表明，在各种小鼠结肠肿瘤模型中，大肠癌细胞中PHD3的过表达可减弱肿瘤的生长和转移。 PHD3独立于其在癌细胞本身中的功能，在人类结肠癌组织的基质巨噬细胞中表达。实际上，遗传丧失功能研究表明，PHD3的丧失特别诱导了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表达的丧失会产生肿瘤抑制作用，而其先天免疫细胞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。在第二个资金期间，我们建议进一步阐明结肠癌细胞和肿瘤相关巨噬细胞中PHD3的可疑双重功能，以及它们对结直肠癌进展的坐标影响。此外，为了评估这些洞察力如何转化为结直肠癌患者药物抑制PHD的潜在应用，我们将评估药理学抑制PHD PHD对大肠肝转移酶扩展的影响，尤其是在手术肝切除术中。