Master Role of Hypoxia in Cancer Progression: Major Insights During ISOTT's Half-Century

On the occasion of ISOTT's half-century, in this chapter, tumour hypoxia (i.e. critically reduced oxygen levels on macro- and microscopic scales), recently classified as an additional hallmark of cancer, its various aetiology-related classifications (diffusion- or perfusion-limitations, hypoxaemic), time-frames of exposure (acute, chronic, cyclic), and different levels (moderate, mild, severe) within and across tumours, and its Janus-face-like role ("dichotomy") in tumour regression (e.g. apoptosis, necrosis) versus "adaptive" tumour progression have been updated and summarised. This latter knowledge is, to a great extent, based on (a) direct, reliable assessments and mapping of the heterogeneous tumour oxygenation status using minimally invasive polarographic pO₂ microsensors in clinical settings since the late 1980s, and (b) the discovery of the hypoxia-inducible factors (HIFs) in the early 1990s. These data have clarified the role of hypoxia in stimulating a variety of biologic responses that mediate cancer progression through changes (a) in the genome (associated with clonal selection and expansion), (b) in the transcriptome, and (c) in the proteome, as well as its role as a barrier to the effectiveness of anti-cancer therapies.