>Chronic stress increases metastasis via neutrophil-mediated changes to the microenvironment

https://www.sciencedirect.com/science/article/abs/pii/S15356...

Summary

Chronic stress is associated with increased risk of metastasis and poor survival in cancer patients, yet the reasons are unclear. We show that chronic stress increases lung metastasis from disseminated cancer cells 2- to 4-fold in mice. Chronic stress significantly alters the lung microenvironment, with fibronectin accumulation, reduced T cell infiltration, and increased neutrophil infiltration. Depleting neutrophils abolishes stress-induced metastasis. Chronic stress shifts normal circadian rhythm of neutrophils and causes increased neutrophil extracellular trap (NET) formation via glucocorticoid release. In mice with neutrophil-specific glucocorticoid receptor deletion, chronic stress fails to increase NETs and metastasis. Furthermore, digesting NETs with DNase I prevents chronic stress-induced metastasis. Together, our data show that glucocorticoids released during chronic stress cause NET formation and establish a metastasis-promoting microenvironment. Therefore, NETs could be targets for preventing metastatic recurrence in cancer patients, many of whom will experience chronic stress due to their disease.

> Mice were exposed to physical restraint stress as previously described (https://www.nature.com/articles/s41586-020-1935-3). Briefly, female mice were restrained in individual, homemade 50 mL Falcon tubes with air holes for 2 hours per day. Mice could move backward and forward slightly in the restraining tube.

I wonder why they only used female mice. In the original methods study about the effect of stress on hair loss both male and female mice are used.

my understanding from the article is that they're working specifically w/ breast cancer, so probably easier w/ females

That's disturbing. Cancer patients undergoing chemotherapy will often be given Lipegfilgrastim to bolster their immune system. It does this by stimulating the production of neutrophils.

Yes, because neutropenia is a limiting factor in how far you can go with certain chemotherapeutic agents, such CDK inhibitors.

...in mice. :^)

And people, I am certain.

Lets wait for the research to investigate this. A lot of research in mice doesn't translate to humans.

I don't think many people who suffer(ed) chronic street will need to see the hard research on humans to confirm it affects your health in a negative way.

Sample size = 1 from me.

That’s pretty different from what the headline is contending, though… Your statement is certainly true, of course, but the article is specifically claiming a link to cancer.

Sure but that's not the claim I replied to.

How are you certain? Chronic stress can be really harmful, but saying that it spreads cancer is a stretch that needs to be scientifically proven. Making mice artificially stressed isn't the way though.

I don't know why you're getting down voted. This is a very important detail.

It is interesting to note that all higher lifeforms have evolved to die (presumably to avoid out-competing their descendants).

From this perspective, mechanisms that prolong life in favourable circumstances but curtail in difficult times, make sense.

> It is interesting to note that all higher lifeforms have evolved to die (presumably to avoid out-competing their descendants).

I think we need to substantiate this more. Where does "higher" lifeform begin? And is this statement really true?

There are trees older than 4k years and some whales become 200 years old.

One of the most interesting thoughts I have read on hacker news in the last several weeks.

I don’t think anything evolved to die. Dying is a prerequisite to evolution. If every individual were to survive, the gene pool would not converge towards more advantageous adaptations. The word “advantageous” means more apt to survive.

Apoptosis is an ordered process. You have in fact evolved to die.

Apoptosis happens at a cellular level and is controlled by higher systems such as cytokines. You haven't evolved to die, but your cells have evolved to die when instructed to.

Isn’t that the same thing?

No. It's all about gamete survival.

This might be more philosophical, but here’s how I think about. Would love to hear your take on it.

Before life, there was only death. At some point, something life-like sprung into existence, and soon died. And then it happened again. At some point it was able to reproduce, and then died.

Death is the default. It was always there. Some things managed to cheat it long enough to reproduce. Those things are alive.

This is why I don’t see that organisms evolved to die. The very first life-like things were dying, before they had the ability to reproduce.

Aging doesn't seem to be inevitable: some animal species live for very long times even hundreds of years. And yet we have a predetermined lifespan far below that. Seems as though that's an purposeful systematic difference etween species that control how long each generation survive before death.

> I don’t think anything evolved to die

Agreed, but..

> Dying is a prerequisite to evolution. If every individual were to survive, the gene pool would not converge towards more advantageous adaptations.

This is kinda wrong. Reproduction is the perquisite for evolution. Evolution does not care much about your "survival" as a whole, especially after you reproduced. In "Survival of the fittest", you can better think of survival on the level of genes, not individuals, for the most part.

The mechanism has not evolved to "curtail life". The changes that happen in the body with activation of the HPA axis and SNS are beneficial in times of stress. They shift glucose towards the muscles, reduce energy use by the digestive system a, and shift the immune system towards innate immunity in order to deal with immediate threats to the body.

> It is interesting to note that all higher lifeforms have evolved to die (presumably to avoid out-competing their descendants).

I need a source on that, because for the most part that's not how evolution works.

At the point of reproduction, the moment genes are passed on, the paternal time of death isn't "known" to natural selection. Generally speaking, there really is no way to put pressure on death like you suggested. Except maybe for some group selection mechanics, where scientific consensus would be far from settled, and it wouldn't qualify for any statement on "all higher lifeforms", anyway.

What's true tho, evolution doesn't care too much about your survival after reproduction, either. So, eg. some early in life adaptations may increase your chances of death later in life - live fast, die young.

But that's really different than saying death has this evolutionary purpose like you suggested. Complicated things just fall apart at some point. That's so much a fact, that large animals like whales and elephants actually do need "anti-cancer" adaptations to bring their plenty of cells into reproductive age.

Also, I think people may be prone to an anachronistic fallacy in regard to dying here. See, 1 in 5 people will die because of cancer, it's a pretty "natural" thing in our lives, but.... human cancer rates are actually mostly down to environmental and lifestyle factors. Before civilization and industrialization cancer was rare. Yes, people live longer to see it happen, but for example lung cancer is almost always attributable to some hazard exposure. Smoking increases your risk by 2000% (!), yet most smokers won't get lung cancer - lung cancer is that rare!

Alcohol, houses on radon soil, highly processed food, VOCs, hexavalent chromium, heavy metals, estrogenic plasticizer, asbestos, sedentary lives, obesity, microplastic, nanoparticles, ... stress. We could have cashed in on maternal and child mortality to fix our stats, but hey: you win, you lose.

Great another thing to worry about…

As someone who has had incurable brain cancer for 7+ years this stresses me out. From a logical perspective, our bodies aren't designed to withstand the kind of emotional turmoil that follows a cancer diagnosis. In nature, we would either pass away quickly to 'unknown' illness or never know that there was anything 'wrong' with us until we met a swift end. Neither options allow the human brain to comprehend what is going on. Modern advancements in technology open up a really challenging area of pyscological science, where we know something is wrong, but I dont believe the brain is fully capable of processing that information. A by-product of that is stress.

Much love your way. I lost a partner that went through it. Modern antidepressants and anti-anxiety medication did seem to help. You are brave to talk about it and I hope more people do.

I don’t see this way of thinking very often and I do think it’s more useful to meditate on it. Thank you for taking the time for this, the silent majority appreciates it even if we can’t find the words.

My friend died from lung cancer caused by too much smoking after losing his job. And handling that is very stressful to me because I am, and others like me are almost in the same boat.

“but as far as the depression and hopelessness associated with cancer, there’s a lot of evidence stemming from Roland Griffiths’ original work from John Hopkins University suggesting strongly that a single dose of psilocybin is extremely effective at helping reduce the depression and anxiety surrounding end of life in cancer patients.”

What's the definition of stress?

Bad hormones elevated to pathological levels at all times and chronic inflammation.

Watch this. https://www.youtube.com/watch?v=eYG0ZuTv5rs

Elevated levels of Cortisol outside the natural time window.

Stress is a natural response to danger. All animals exhibit stress. It is manifested as the hormone cortisol in the bloodstream. Cortisol shuts down non-essential operations so that the animal can escape the danger. One of them is digestion, another is the immune system. Once the animal is safe, the body comes back to balance.

The problem is with chronic stress. In humans it is the chronic social stress. The digestion is impaired, the immune system is impaired.

I am not too clear about the connection between cancer cells and immune system response. It is clear the primary correlation between stress and immune deficiency is improper regulation of neurotransmitter GABA. Since that connection is firmly known it could be that improper immune system regulation either spreads the conditions that allow cancer formation or reduces the immune response to fighting cancer.

The primary cause of anxiety is chronic stress. Chronic stress most typically occurs when a fear or aggression memory is stamped in the amygdala in the brain. The left and right amygdalas are asymmetrical and process different tasks in humans, by the way. In a healthy person a fear memory is generated in the amygdala which loops through other areas of the limbic system before coming back to the amygdala with additional emotional processing, but before looping more the fear process is halted by flooding the amygdala with a suppressor, GABA. In unhealthy people GABA is not released into the process at appropriate moments resulting in a run away loop of building negative emotions. GABA is also produced, as a regulator, by the immune system.

As an aside the immune system also produces another neurotransmitter responsible for both immune system excitement that plays an unrelated role of emotional motivation in the brain. That is why antihistamines medications make people drowsy, because suppressing that neurotransmitter via medication occurs in utero.

> As an aside the immune system also produces another neurotransmitter responsible for both immune system excitement that plays an unrelated role of emotional motivation in the brain. That is why antihistamines medications make people drowsy

You mean histamine? I think antihistamines make people drowsy, because histamine signaling at the H1-Receptor is involved with regulation of the circadian rhythm [1][2]. As far as I know, histamine is released, as part of the immune system, by mast cells, which have to be triggered by IgE (parasite / "macro stuff" / "allergy") antibodies.

Neither the "H1 receptor", "H1 antagonist", "Histamine", "Tuberomammillary nucleus" nor "Mast cell" Wikipedia article match "GABA".

> because suppressing that neurotransmitter via medication occurs in utero.

What does this even mean? I mean, I don't know...

[1] https://en.wikipedia.org/wiki/Histamine_H1_receptor#Neurophy...

[2] https://en.wikipedia.org/wiki/Histamine#Sleep-wake_regulatio...

TIL: One more thing to stress about!

So like Robert Sapolsky was right this whole time?

https://youtu.be/eYG0ZuTv5rs?si=6rxFQEa0c8zBroqD

https://www.goodreads.com/en/book/show/327

The full length video of his is definitely worth a watch, but if anyone's short on time, there's quite a good much shorter version focussing more on the hierarchy/alpha male side of it -

https://www.youtube.com/watch?v=A4UMyTnlaMY

Yes, we might have different stresses as a species now, but I'm not sure we have any more stress than we had thousands of years ago.

Thousands of years ago doesn’t seem a good reference point. With advances in science, technology, better shelters and more accessible food - we absolutely should have way less stress today.

Although...

> anthropologists have found that hunter-gatherers tend to have significantly more leisure time than people in more complex societies.

https://en.wikipedia.org/wiki/Leisure#Cultural_differences

I would also postulate that the average human was happier 20000 years ago than the average human today. I also think that an average duck is happier than an average human.

> I also think that an average duck is happier than an average human.

Perhaps being able to think doesn't help much when it comes to happiness. Thinking is useful practically but it's as if you have to suppress it in order to experience happiness.

Is duck not able to think?

I heard they are all quacks.

> I also think that an average duck is happier than an average human.

You should read a bit about their sex lives...

My snarky remark would be that with advances in capitalism, we’ve found ever more ways to generate stress.

The less snarky remark would be that Robert Sapolsky has done plenty of research on stress responses in primates and found that the single largest predictor of high stress responses is inequality, which our modern times do seem to generate in abundance.

Humans did not have a long time span thousands of years ago as well…

The majority of the human race lives with chronic stress. Spreading depends on the cancer and how quick it is caught, the worrying part is barely even negligible - as they point out early on. Can't wait for part two on why happy people live longer. Hokum.

Lesson I learned from my first adult job: money might not buy happiness, but being broke sure is stressful.

i actually felt way more stressed when i started making more money because it opened up way more possibilities which led to analysis paralysis.

Yes, I did say my first adult job -- that's where I went from scrounging paycheck to paycheck to make rent, to being comfortable setting up autopay for my bills. However, I've never been payed at the analysis-paralysis level.

There's a sweet spot, I think, between barely scraping by, and keeping up with the Joneses.

In the near future someone will conduct a scientific study on how people who feel sick generally don't live as long

I did see this recently:

"An unhealthy obsession with sickness increases risk of dying, study says"

https://www.washingtonpost.com/nation/2023/12/25/hypochondri...

Obviously. Anyone who has been severely stressed knows it's killing them.....except the doctors who cannot sell you something from their pill sponsors

My stress based disorder is cluster headaches and they literally feel like death and all I can say is don't rely on doctors to help, diet changes are not in most western based docs playbooks, drugs which cover up and masks the problems are, try heavily modifying diet, start going into ketosis and see if you feel better after a couple months. It took me 8 years and the best healthcare around to reach this point. Cold shock seems to quite stress/inflammation as well. These things are freely available.

Other non drug alternatives: Meditation, acupuncture, camping, horse back riding, walks, runs, swimming all seem effective at lowering stress as well from my exp.

A friend of mine who had the same also tried everything.

Healthy livestyle in general and meditation are good obviously - but in his case drugs apparently did help: LSD and psybicilin. To let go of some stress inducing thought patterns. ( he did use lots of it for some time) So in his case it was largely a success - but of course it can also go very wrong. So I am not recommending it, just sharing a anecdota of a case where it was helpful. As far as I understood, when you are experiencing cluster headaches - you are willing to try everything, to not experience it again, so all the best to you and anyone else experiencing it.

> Cold shock seems to quite stress/inflammation as well.

I am having trouble parsing this sentence. Did you mean "quiet"?

Stop lying. Diet is literally the first thing a doctor will tell you to change.

In the UK, doctors will prescribe exercise, therapy, meditation, group activities as well as drugs if appropriate. What else can they do?

The issue isn’t the doctors, it’s that society, or even just the human condition, often makes it impossible to eliminate the source of chronic stress.

> The issue isn’t the doctors, it’s that society, or even just the human condition, often makes it impossible to eliminate the source of chronic stress.

Indeed, all my chronic stress can immediately be solved with large quantities of money.

I don’t know your specific situation but this is a pretty common fallacy that has been undermined by studies that show that most people do not experience increased happiness beyond income levels that cover their necessities and a bit more (it used to be around $75k/year in the US and with inflation might be around $100k now - I.e. having $5m / year isn’t going to be as impactful as you’d think. Money isn’t a panacea, and “wherever you go, there you are”).

I thought this way too, and then made a bunch of money to the point I no longer had to work after around 35. I can tell you first hand with my n=1 study that more money is not very impactful. You’re still you, with all the hangups and other things to work through. Focus on achieving income to meet your necessities and a bit more and then put your energy into relationships and your health and fitness, and hobbies. More money at the expense of these other things is a fool’s bargain.

That study was flawed by the way, it turns out that more money does increase happiness.

So 75k is more the floor not a ceiling.

All it really supports is having universal basic income.

As I said, all my chronic stress can immediately be resolved with a large amount of money, since the lack of is the direct cause of that stress.

I appreciate the “money doesn’t buy happiness” advice, even if it comes from someone that was financially independent at 35 - good for you! - but you are making some _wild_ assumptions about the causes of my chronic stress, none of which have to do with my hangups, or hobbies, or anything else like that.

I have had financial lows, with “low” being “homeless at 17” and I have had some financial highs, with “high” being “impactful startup exit”. I have never made assumptions about what would solve someone else’s’ problems, and I would dream of making the presumption of telling them that the thing they have identified as their issue isn’t really their issue.

$5m a year would make me plenty happy, thanks, and would absolutely allow me to focus on my health and fitness, and take up a hobby. Right now, there are not enough hours in the day for any of those kind of luxuries.

What do you propose the doctors should do instead in this situation?

It's just a petulant rant against authority figures. Ignore stuff like that.

Well at least they’re not prescribing you benzos.

Reading the "Myth of Normal" by Gabor Maté opened my eyes for this as a possible explanation.

I highly recommend this for a read on how stress alters the body.