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

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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.