Hypoxia-Driven Adenosine Accumulation: A Crucial Microenvironmental Factor Promoting Tumor Progression.

Systematic studies on the oxygenation status of solid tumors have shown that the development of hypoxic/anoxic tissue subvolumes is a pathophysiological trait in a wide range of human malignancies. As a result of this characteristic property, adenosine (ADO) accumulation (range: 50-100 μM) occurs caused by intra- and extracellular generation of ADO. Extracellular nucleotide catabolism by hypoxia-/HIF-1α-sensitive, membrane-associated ecto-5'-nucleotidases most probably is the major source of ADO in the halo of cancer cells upon specific genetic alterations taking place during tumor growth. Extracellular ADO can act through autocrine and paracrine pathways following receptor-binding and involving different intracellular signalling cascades. Hypoxia-driven receptor activation can lead to a broad spectrum of strong immune-suppressive properties facilitating tumor escape from immune control (e.g., inhibition of CD4+, CD8+, NK and dendritic cells, stimulation of Treg cells). In addition, tumor growth and progression is promoted by ADO-driven direct stimulation of tumor cell proliferation, migration, invasion, metastatic dissemination, and an increase in the production of molecules stimulating tumor angiogenesis. Hypoxia- driven ADO accumulation in the tumor microenvironment thus plays a critical role in tumor growth and progression at multiple pathophysiological levels.