Hypoxia induced cancer stem cell enrichment promotes resistance to ADT.

[pjoshea13]

New study below.

One of the myths we regularly run into is that "cancer hates oxygen". People buy into dubious ways of delivering more oxygen to their tumors.

A tumor will eventually outgrow its blood (& hence oxygen) supply. A lack of oxygen (hypoxia) will result in the generation of hypoxia-inducible factors [HIFs]. In PCa, the appearance of HIFs lead to a growth factor (vascular endothelial growth factor [VEGF] & the building of new blood vessels (angiogenesis). Cancer does not appear to hate oxygen.

The problem with HIFs is that they trigger the ultimate cell survival response. HIFs are the main reason for treatment resistance. The best way to avoid HIFs is to improve the oxygen supply.

Unfortunately for men with PCa, the standard treatment of ADT lowers the red blood cell [RBC] count. Oxygen is carried by hemoglobin in RBCs.

The obvious solution is to increase blood flow via a nitroglycerin patch. Glyceryl trinitrate [GTN] has been used since 1878. Ironically, Alfred Nobel was an early beneficiary. In the U.S. there are about three million prescriptions annually.

GTN works by producing nitric oxide, which dilates blood vessels.

See Siemens (2009) [2].

"We report the first clinical trial of a GTN patch in patients with prostate cancer. The prolongation of the PSADT and the safety of the drug, coupled with the corresponding preclinical in vitro and in vivo data documenting the ability of nitric oxide to attenuate hypoxia-induced progression of prostate cancer, warrant further testing in a placebo-controlled study."

From the new paper [1]:

"Here in we highlight how activation of HIF signalling, in response to hypoxic conditions within the tumour microenvironment, results in the expression of genes associated with stemness and EMT promoting {prostate cancer stem cells} emergence which ultimately drives tumour relapse to CRPC."

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/315...

Androgen deprivation therapy (ADT) is the main treatment to prolong survival in advance stage prostate cancer (PCa) but associated resistance leads to the development of terminal castrate resistant PCa (CRPC). Current research demonstrates a critical role of prostate cancer stem cells (PCSC) in the development of treatment resistance and subsequent disease progression. Despite uncertainty surrounding the origin of these cells, studies clearly show they are associated with poorer outcomes and that ADT significantly enhances their numbers. Here in we highlight how activation of HIF signalling, in response to hypoxic conditions within the tumour microenvironment, results in the expression of genes associated with stemness and EMT promoting PCSC emergence which ultimately drives tumour relapse to CRPC. Hypoxic conditions are not only enhanced by ADT but the associated decrease in AR activation also promotes PI3K/AKT signalling which actively enhances HIF and its effects on PCSC's. Furthermore, emerging evidence now indicates that HIF-2α, rather than the commonly considered HIF-1α, is the main family member that drives PCSC emergence. Taken together this clearly identifies HIF and associated pathways as key targets for new therapeutic strategies that could potentially prevent or slow PCSC promoted resistance to ADT, thus holding potential to prolong patient survival.

Copyright © 2019. Published by Elsevier Inc.

KEYWORDS:

Androgen deprivation therapy; Cancer Stem cells; EMT; Hypoxia; Prostate Cancer

PMID: 31521707 DOI: 10.1016/j.steroids.2019.108497

[2] ncbi.nlm.nih.gov/pubmed/194...

[Tall_Allen]

Why do you call it a myth? Cancer cells are better able to survive oxygen depletion than healthy cells - it's not a myth.

[pjoshea13 in reply to Tall_Allen]

Small tumors do quite well under normoxic conditions. Hypoxia is not required for their survival. Hypoxia occurs when tumors outgrow their blood supply. The hallmark of hypoxia is the generation of VEGF to extend the blood supply.

Hypoxia does trigger other survival factors that lead to treatment resistance, so it may seem that the cancer prefers hypoxic conditions, but that would put the cart before the horse.

By improving the supply of oxygen, we seek to prevent the disastrous consequences of hypoxia. It's a paradox really, since the extra oxygen will not kill the cancer, but will simply help it to maintain the status quo.

And yet people spend money on hyperbaric oxygen therapy in the hope that the oxygen will kill their cancer.

-Patrick

[Tall_Allen in reply to pjoshea13]

I disagree wrt prostate cancer. It thrives in particularly hypoxic conditions. The environment it preferentially grows in - lymph nodes, bone, and prostate are poorly oxygenated. VEGF is not the hallmark of hypoxia - there are other biomarkers that can be used, and certain scans are in clinical trials. In fact, VEGF inhibitors have been found to be ineffective in PC.

Improving oxygen supply favors healthy cells over cancerous cells, and because of tissue effects, healthy cells can help keep the cancer in check. Overcoming hypoxia is a goal of hyperthermal therapy and of radiation fractionation or both. Hyperbaric oxygen is used to repair healthy tissue damaged by radiation - I haven't heard of any curative effects on the cancer. I believe that aerobic exercise just before radiation and breathing 100% oxygen during treatment may enhance its benefits - I've proposed a clinical trial - we'll see if I can whip up enthusiasm.

[pjoshea13 in reply to Tall_Allen]

You claim that "VEGF is not the hallmark of hypoxia".

"To our knowledge, this is the first study demonstrating a significant association between increasing levels of hypoxia and increased expression of the angiogenesis marker VEGF in human prostate carcinoma."

ncbi.nlm.nih.gov/pubmed/113...

"VEGF expression is up-regulated in response to hypoxia and this is mediated by the stabilization of the transcription factor hypoxia-inducible factor 1 (HIF-1α) that up-regulates transcription of VEGF via binding at HIF-Responsive elements."

ncbi.nlm.nih.gov/pmc/articl...

-Patrick

[Tall_Allen in reply to pjoshea13]

I guess it depends on what you mean by a "hallmark." I took it to mean a biomarker that signals hypoxia and nothing else. There are better ways of identifying tumor hypoxia that are specific only to hyypoxia - that is what I would mean by a "hallmark." All prostate tumors, whether hypoxic or not, use VEGF to grow a blood supply. Sadly, anti-VEGF medicines do not work on prostate cancer.

[pjoshea13 in reply to Tall_Allen]

What I meant by hallmark is that hypoxia invariably leads to VEGF (via HIF1alpha).

I doubt that VEGF would be triggered in the absence of HIF1alpha.

My original point was that when tumors become hypoxic, their first response is to build blood vessels to increase the oxygen supply - they 'want' to be normoxic.

-Patrick

[Tall_Allen in reply to pjoshea13]

That isn't how it works. All solid tumors, hypoxic or not, release VEGF to form a blood supply. Healthy non-hypoxic tissues stimulate VEGF too- it's part of how tissues survive. Indeed, even BPH overstimulates VEGF release. VEGF is a normally active gene - not a "hallmark" of hypoxia.

[pjoshea13 in reply to Tall_Allen]

One last attempt to convince you that hypoxia-induced angiogenesis is key:

"We deleted the hypoxia-responsive transcription factor HIF-1α in endothelial cells (EC) to determine its role during neovascularization. We found that loss of HIF-1α inhibits a number of important parameters of EC behavior during angiogenesis: these include proliferation, chemotaxis, extracellular matrix penetration, and wound healing. Most strikingly, loss of HIF-1α in EC results in a profound inhibition of blood vessel growth in solid tumors. These phenomena are all linked to a decreased level of VEGF expression and loss of autocrine response of VEGFR-2 in HIF-1α null EC. We thus show that a HIF-1α-driven, VEGF-mediated autocrine loop in EC is an essential component of solid tumor angiogenesis."

cell.com/cancer-cell/fullte...

-Patrick

[Tall_Allen in reply to pjoshea13]

There is no doubt that hypoxia induces VEGF expression, but so do a lot of other things, including normal tissue growth.

[Garp41]

PJ,

Would beet powder or L-Citrulline do about the same......increase Nitric Oxide?

Doug

[pjoshea13 in reply to Garp41]

Doug,

Beets have betaine, which is a methyl donor, so I wouldn't use it.

I doubt that L-Citrulline will help, but perhaps someone will correct me.

-Patrick

[GeorgeGlass in reply to pjoshea13]

Arginine combined with citrulline does increase nitric oxide and vessel dilation, but it only does it for a few hours. The patch that Patrick mentioned, does it in a time-released way for the entire day. My question is - does the patch give you bad headaches or other side effects, and does your body develop a tolerance to it over time, thus making it less effective?

[pjoshea13 in reply to GeorgeGlass]

Hi George,

Excellent questions.

In terms of resistance precautions, I try to remember to ditch the little invisible patch before bed; and try to remember to put a new one on the next day.

On the whole, I have not had headaches, but it is possible that I have had a few because of the nitro. When in doubt, take the patch off. If it is a problem, perhaps a lower dose will help. With less NO in circulation, blood vessels to the brain would be not quite as dilated.

-Patrick

[GeorgeGlass in reply to pjoshea13]

Makes sense, I just found this on the web, that taking it off for 10-12 hours near bedtime helps fight off tolerance to it.

I have not got headaches from the arginine citrulline combo during workouts, not have I gotten a headache from the Rise nitro brew coffee I drank yesterday for the first time. My energy yesterday and today is through the roof, and it's not very jittery either. Must be due to the nitro brew formula.

The patches have difference dosage levels huh? Do you use Nitro-Dur brand patch?

[henukit]

That's probably the reason for better outcomes when one is engaged in physical activity while on ADT is it should improve blood circulation and reduce hypoxia.

I also wonder if it makes a difference to use GTN patches during chemo and radiation to impvoe oxygen supply to the tumor sites and increase therapy efficiency.

[GeorgeGlass]

this makes me wonder if intermittent ADT would increase longevity, presuming that the breaks were administered at the appropriate time, and not staying off ADT for too long, before starting on it again. MY MO said that he thinks the continuous group in the study, did better because patients and MOs let the cancer get out of control before starting up again, on the ADT. What do you think Patrick?

[GeorgeGlass]

This stood out to me in the study findings: "Furthermore, emerging evidence now indicates that HIF-2α, rather than the commonly considered HIF-1α, is the main family member that drives PCSC emergence. "

What works against HIF-2a? I read that resveratrol foods help to fight HIF-1a but I don't know what do against HIF-2a.