Cyclic Hypoxia: An Update on Its Characteristics, Methods to Measure It and Biological Implications in Cancer

Abstract

Regions of hypoxia occur in most if not all solid cancers. Although the presence of tumor hypoxia is a common occurrence, the levels of hypoxia and proportion of the tumor that are hypoxic vary significantly. Importantly, even within tumors, oxygen levels fluctuate due to changes in red blood cell flux, vascular remodeling and thermoregulation. Together, this leads to cyclic or intermittent hypoxia. Tumor hypoxia predicts for poor patient outcome, in part due to increased resistance to all standard therapies. However, it is less clear how cyclic hypoxia impacts therapy response. Here, we discuss the causes of cyclic hypoxia and, importantly, which imaging modalities are best suited to detecting cyclic vs. chronic hypoxia. In addition, we provide a comparison of the biological response to chronic and cyclic hypoxia, including how the levels of reactive oxygen species and HIF-1 are likely impacted. Together, we highlight the importance of remembering that tumor hypoxia is not a static condition and that the fluctuations in oxygen levels have significant biological consequences.

Keywords: cyclic; hypoxia; intermittent; transient.

Figure 1

Window chamber data illustrating relatively slow fluctuations in tumor oxygenation and redox ratio. In this study, nude mice with window chambers were transplanted with FaDu head and neck cancer cells. After several days of growth, hemoglobin saturation Hb_sat and redox ratio (ratio of fluorescence intensities of FAD and NADH) were measured every 6 h for 36 h. (A) Regions of interest selected for analysis. (B) Paired Hb_sat and Redox ratios from one tumor. Note particularly the region indicated by the blue arrow at 0 and 12h. This region shows fluctuation in both parameters around a small network of microvessels. (C,D). Time course of changes in Redox ratio and Hbsat. (E) Over all tumors studied, there was a linear relationship between these two parameters, illustrating that there is a link between oxygen delivery and demand. In the analogy to tides and waves in Figure 2, these slow fluctuations are the tides. Panels A–D are from Skala et al. [13]. (DOI: 10.1117/1.3285584) CC-BY. Panel E is derived from the data for Panels A–D, but has not been previously published.

Figure 2

Tides and waves provide an analogy to the kinetics of cycling hypoxia. As depicted in Figure 1, the slow (quasi-steady state) fluctuations in tissue pO₂, that occur over hours are analogous to tides. (Upper panel). Map of hemoglobin saturation across a tumor growing in a window chamber (blue = low saturation, orange to red = high saturation). The faster cycles, occurring 2–5 times per hour are analogous to waves. (Lower Left) In a region where the steady state pO₂ (tide) is low, the higher frequency fluctuations (waves) in oxygen delivery will lead to fluctuations in the extent of tissue hypoxia, depicted by the island of hypoxia. (Lower Right) When the overall oxygen field is high, the waves have less of an influence on the extent of cycling hypoxia. Reproduced from Dewhirst [4], with permission from the publisher @ 2021 Radiation Research Society.

Figure 3

The effect of cyclic hypoxia on different stages in metastasis. (A) number of studies have demonstrated that exposure to cyclic hypoxia drives metastasis and importantly, that this occurs at all the key stages of the process. A. EMT/stemness [79,80,81,85,86,88]. (B) Invasion/migration [78,80,81,82,84]. (C) Modulation of the extracellular matrix (ECM) [160]. (D) Survival in blood circulation [89]. (E) Proliferation in target organ [86,89,99,103,104,105,106,159].