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

[SNT Gatchaman]

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.

Link | PDF (Cancers)

 

[SNT Gatchaman]

Hypoxia induces a cellular adaptive response that elevates the expression of the transcription factors called hypoxia-inducible factors (HIFs) that activate the global gene expression changes in both non-malignant and cancer cells. HIF-1 and HIF-2 promote increases in the lymphangiogenic and angiogenic responses as well as metabolic changes that lead to a shift to glycolysis.

These changes include the deregulation of endoplasmic reticulum (ER) homeostasis, and the subsequent perturbations in protein folding and secretion. The potential for erratic protein folding can also lead to another specialized stress response signaling pathway called the unfolded protein response (UPR).

posttranslational folding of the proteins is oxygen-dependent. Hypoxia limits the activity of the oxygen-dependent ER-localized oxidoreductase (ERO1α), and this leads to the deregulation of the posttranslational protein modifications and thereby, promotes ER stress.

Notably, the lipid desaturation processes that are necessary for maintaining ER membrane homeostasis are oxygen-dependent as well.

The cellular oxygen levels also influence the protein stability of the HIF transcription factors.
Hypoxia induces a cellular adaptive response that elevates the expression of the transcription factors called hypoxia-inducible factors (HIFs) that activate the global gene expression changes in both non-malignant and cancer cells. HIF-1 and HIF-2 promote increases in the lymphangiogenic and angiogenic responses as well as metabolic changes that lead to a shift to glycolysis.

These changes include the deregulation of endoplasmic reticulum (ER) homeostasis, and the subsequent perturbations in protein folding and secretion. The potential for erratic protein folding can also lead to another specialized stress response signaling pathway called the unfolded protein response (UPR).

posttranslational folding of the proteins is oxygen-dependent. Hypoxia limits the activity of the oxygen-dependent ER-localized oxidoreductase (ERO1α), and this leads to the deregulation of the posttranslational protein modifications and thereby, promotes ER stress.

Notably, the lipid desaturation processes that are necessary for maintaining ER membrane homeostasis are oxygen-dependent as well.

The cellular oxygen levels also influence the protein stability of the HIF transcription factors.

 

[SNT Gatchaman]

One of the important functions of HIFs is to prevent the conversion of pyruvate to acetyl-Co-A and to increase the expression of glucose transporters and glycolytic enzymes to emphasize the glycolytic pathway. The HIFs also down-regulate cytochrome c oxidase (COX) subunit composition expression

Hypoxia is only one of numerous processes that can induce an ER stress, and other ways include a nutrient deprivation, acidosis, a high metabolic demand, the processes of reactive oxygen species, an augmented secretory capacity, the deregulation of transcription and translation

One of the important consequences of temporal normoxia in hypoxic cells is the extensive ROS accumulation upon the reintroduction of oxygen that is also observed during hypoxia-reoxygenation injury and ischemia-reperfusion injury. This results in extensive UPR and UPRmt activation

Taken together, the crosstalk between HIF signaling and UPR clearly demonstrates that the interaction between these pathways is dynamic.

 

[SNT Gatchaman]

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.

 

[SNT Gatchaman]

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.

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 —

Martin Kraeter — “We’ve seen in patients with Covid-19 and Long Covid that they have lots of red blood cells that don’t deform properly anymore,” he told the Herald.
“That means they can’t take up oxygen and makes the blood more sticky - or more like honey than water – and we’re still seeing this in some of the patients in our study cohort, long after they’ve recovered from the primary disease.”

 

[Hutan]

Interesting, thanks SNT.

I think intermittent hypoxia is a significant part of the illness I have. The numbness in my arms that comes when driving or hanging out washing, or the frequency of waking with a completely numb limb is not normal. The postural orthostatic tachycardia, the pulse pressure issues, the bulging veins, the way extremities will become and stay very cold...

(I drafted this post a while back. Coincidentally, I just got up from sitting and my foot was numb. As I put my weight onto the leg, the foot flopped underneath, with the top of the foot making contact with the floor and making three loud cracks. So, I'm now sitting on my bed, with an icepack on my foot. The foot is functioning and I expect it will be fine, just some pain for a while and some bruising. But, the frequency of numbness is definitely not normal.)