The Role of the Hypoxia-Related Unfolded Protein Response UPR in the Tumor Microenvironment, 2022, Bartoszewska et al.

The Role of the Hypoxia-Related Unfolded Protein Response UPR in the Tumor Microenvironment
Bartoszewska, Sylwia; Collawn, James F.; Bartoszewski, Rafal

Despite our understanding of the unfolded protein response (UPR) pathways, the crosstalk between the UPR and the complex signaling networks that different cancers utilize for cell survival remains to be, in most cases, a difficult research barrier. A major problem is the constant variability of different cancer types and the different stages of cancer as well as the complexity of the tumor microenvironments (TME). This complexity often leads to apparently contradictory results. Furthermore, the majority of the studies that have been conducted have utilized two-dimensional in vitro cultures of cancer cells that were exposed to continuous hypoxia, and this approach may not mimic the dynamic and cyclic conditions that are found in solid tumors.

Here, we discuss the role of intermittent hypoxia, one of inducers of the UPR in the cellular component of TME, and the way in which intermittent hypoxia induces high levels of reactive oxygen species, the activation of the UPR, and the way in which cancer cells modulate the UPR to aid in their survival. Although the past decade has resulted in defining the complex, novel non-coding RNA-based regulatory networks that modulate the means by which hypoxia influences the UPR, we are now just to beginning to understand some of the connections between hypoxia, the UPR, and the TME.

Simple Summary: The complex signaling networks that different cancers utilize for cell survival remain poorly understood. A major problem is the complexity of the tumor microenvironments (TME). Here, we discuss the role of intermittent hypoxia as one of the inducers of the UPR in the TME and the related implications of it for both cancer progression and therapeutic approaches.

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We've been discussing ER stress, most recently with the WASF3 findings. I found this paper interesting, looking at the dynamic effect of intermittent hypoxia on ER stress (in this case in cancer, where tumours have unstable blood supplies).

It occurred to me that if muscle cells were subject to intermittent hypoxia and normoxia (eg at rest vs with exercise, in the context of an impaired microcirculation) that might predispose to the increased ER stress being described here in tumours. We've had papers describing capillary rarefaction in LC, so perhaps this could be an induced blood supply fragility through some as yet unestablished mechanism.

(Probably also worth keeping this concept in mind if microclots were subsequently replicated/validated. I would imagine they would cause quite random fluctuations in cellular oxygenation across tissue regions).

@DMissa I wonder if you might be interested in this paper, if not already on radar.

 

That mechanism might also not involve an impairment of the capillaries themselves, but instead be an inherent problem in blood, especially RBCs, ie decreased deformability. Early ME research showed changes in RBC deformability and recent ME papers and now new LC research shows similar findings, albeit not yet published —