We aim at understanding the signaling roles of hypoxia inducible factor-1α and -2 α (HIF-1α/HIF-2 α) in macrophages and tumor cells during macrophage polarization towards tumor-associated macrophages (TAM). We propose that the macrophage phenotype shift towards a tumor promoting cell type is affected by HIF-1α/HIF-2 α, which will be analyzed by using cells derived from HIF-1α/HIF-2 α conditional knockout mice. We explore how hypoxic signaling pathways are affected by nitric oxide (NO) and how this interaction affects pro- vs. anti-inflammatory signal transmission in macrophages in vitro as well as in vivo using an experimental tumor breast model (PyMT). During the macrophage phenotype shift elicited by hypoxia and/or NO we assume epigenetic mechanisms to be involved, considering that some histone demethylases function as Fe(II) dioxygenases and thus, sharing catalytic properties with PHDs (prolylhydroxylases) that are targeted by either hypoxia and/or NO.

Links:

Institute of Biochemistry I (http://www.pathobiochemie1.de/)