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

低氧诱导因子（hypoxia -inducible factors, hif）是适应性缺氧反应中的转录主调控因子，通过改变参与肿瘤细胞存活、增殖、代谢、血管生成和转移的众多靶基因的表达来影响肿瘤生长。HIF脯氨酸羟化酶（PHD1， PHD2和PHD3）是调节HIF活性的分子氧传感器。由于这些PHD酶可以被药物抑制剂抑制，它们是潜在的治疗靶点。具体来说，目前的研究表明，抑制博士学位可能会改善主要肝切除术后的肝功能，这是临床处理结直肠肝转移的基石。在第一个资助期获得的数据显示，与健康肠道粘膜相比，人类结直肠癌标本中PHD3（但不包括PHD1或PHD2）的表达下调，并且PHD3的低肿瘤表达与远处转移的频率增加相关。功能遗传学分析一致地显示，在各种小鼠结肠肿瘤模型中，结直肠癌细胞中PHD3的过表达减弱了肿瘤的生长和转移。独立于其在癌细胞中的功能，PHD3在人结直肠癌组织的巨噬细胞间质中表达。事实上，基因功能缺失的研究表明，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，phd3在肿瘤细胞中的表达缺失具有肿瘤抑制作用，而其在先天免疫细胞中的表达可能独立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，我们将进一步阐明PHD3在结肠癌细胞和肿瘤相关巨噬细胞中的双重功能，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物博士抑制在结直肠癌患者中的潜在应用，我们将评估药物博士抑制对结直肠癌肝转移扩大的影响，特别是在手术肝切除术的情况下。

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.