The role of hypoxia in shaping the recruitment of proangiogenic and immunosuppressive cells in the tumor microenvironment.

Hypoxia characterizes growing tumors and contributes significantly to their aggressiveness. Hypoxia-inducible factors (HIFs 1 and 2) are stabilized and act differentially as transcription factors on tumor growth and are responsible for important cancer hallmarks such as pathologic angiogenesis, cellular proliferation, apoptosis, differentiation and genetic instability as well as affecting tumor metabolism, tumor immune responses, invasion and metastasis. Taking into account the tumor tissue as a whole and considering the interplay of the various partners which react with hypoxia in the tumor site lead to reconsideration of the treatment strategies. Key limitations of treatment success result from the adaptation to the hypoxic milieu sustained by tumor anarchic angiogenesis. This raises immune tolerance by influencing the recruitment of immunosuppressive cells as bone marrow derived suppressor cells (MDSC) or by impairing the infiltration and killing of tumor cells by cytotoxic cells at the level of the endothelial cell wall of the hypoxic tumor vessels, as summarized in the schematic abstract.