sit down, relax, chill out--stress response encourages metastases (can be blocked) in

[Lani]

mice, at least



Stress accelerates breast cancer progression in mice
[Eureka News Service]
Chronic stress acts as a sort of fertilizer that feeds breast cancer progression, significantly accelerating the spread of disease in animal models, researchers at UCLA's Jonsson Comprehensive Cancer Center have found.

Researchers discovered that stress is biologically reprogramming the immune cells that are trying to fight the cancer, transforming them instead from soldiers protecting the body against disease into aiders and abettors. The study found a 30-fold increase in cancer spread throughout the bodies of stressed mice compared to those that were not stressed.

It's long been thought that stress fuels cancer growth in humans. This study provides a model that not only demonstrates that stress can speed up cancer progression, but also details the pathway used to change the biology of immune cells that inadvertently promote the spread of cancer to distant organs, where it is much harder to treat.

The study appears in the Sept. 15, 2010 issue of the peer-reviewed journal Cancer Research.

"What we showed for the first time is that chronic stress causes cancer cells to escape from the primary tumor and colonize distant organs," said Erica Sloan, a Jonsson Cancer Center scientist, first author of the study and a researcher with the Cousins Center for Psychoneuroimmunology. "We not only showed that this happens, but we showed how stress talks to the tumor and helps it to spread."

In addition to documenting the effects of stress on cancer metastasis, the researchers were also able to block those effects by treating stressed animals with drugs that block the nervous system's reprogramming of the metastasis-promoting immune cells, called macrophages.

Beta blockers, used in this study to shut down the stress pathways in the mice, are currently being examined in several large breast cancer databases for their role in potential prevention of recurrence and cancer spread, said Dr. Patricia Ganz, director of cancer prevention and control research at UCLA's Jonsson Comprehensive Cancer Center. If preliminary findings indicate benefit, early phase clinical trials are being considered at the Jonsson Cancer Center testing beta blockers as a means of preventing breast cancer recurrence. Other healthy lifestyle behaviors may also influence the biological pathways described in the study, such as exercise and stress reduction techniques.

"We're going to be focusing on younger women, because they may have a multitude of things weighing on them when they're diagnosed with breast cancer. Younger women have more significant life demands and typically are under more stress," Ganz said.

Ganz said her proposed research will focus on "host factors," or things affecting the patient, that may be aiding the cancer progression and could help explain why a group of patients with the same type and stage of disease have varying rates of recurrence and cancer spread.

"This study provides evidence for a biological relationship between stress and cancer progression and identifies targets for intervention in the host environment," Ganz said. "Because of this study, we may be able to say to a patient in the future that if you follow this exercise regimen, meditative practice or take this pill every day it will help prevent recurrence of your cancer. We can now test these potential interventions in the animal model and move those that are effective into the clinic."

In Sloan's study, mice with breast cancer were divided into two groups. One group of mice was confined in a small area for a short period of time every day for two weeks, while the other group was not. The breast cancer cells were genetically engineered to include the luciferase gene, which is the molecule that makes a firefly glow. The growth and spread of the cancer in the mice was monitored using sensitive cameras that can pick up the luciferase signal and allowed Sloan and her team to observe both the development of primary tumors and the spread of metastases throughout the body, said Steven Cole, an associate professor of hematology/oncology, a Jonsson Cancer Center researcher and senior author of the study.

What was interesting, Cole said, was that the primary tumors did not seem to be affected by stress and grew similarly in both groups of mice. However, the stressed animals showed significantly more metastases throughout the body than did the control group. The cancer, in effect, acted differently in the stressed mice.

"This study is not saying that stress causes cancer, but it does show that stress can help support cancer once it has developed," Cole said. "Stress helps the cancer climb over the fence and get out into the big, wide world of the rest of the body."

Cole said Sloan detailed the biology of the stress-induced changes in the cancer cells along every step of the pathway, providing a road map by which stress promotes cancer metastasis. Additionally, she proved that using beta blockers in stressed mice prevented the same cancer progression seen in the stressed mice that did not receive medication.

When cancer occurs, the immune system sends out macrophages to try to repair the tissue damage caused by uncontrolled growth of cancer cells. The macrophages, in an attempt to help, turn on inflammation genes that are part of the normal immune response to injury. However, the cancer cells feed on the growth factors involved in a normal immune response. Blood vessels that are grown to aid healing instead feed the cancer the oxygen and nutrients it needs to grow and spread, and the extra cellular matrix, which provides structural support for normal cells, is attacked during the immune response, In Sloan's study, mice with breast cancer were divided into two groups. One group of mice was confined in a small area for a short period of time every day for two weeks, while the other group was not. helping the cancer cells escape from the primary tumor and spread to distant parts of the body.

"Many of the genes that promote cancer metastasis get turned on during the immune response by macrophages," Cole said. "This study shows that stress signaling from the sympathetic nervous system enhances the recruitment of macrophages into the primary tumor, and increases their expression of immune response genes that inadvertently facilitate the escape of cancer cells into other parts of the body."

Sloan showed that the beta blockers prevented the macrophages from hearing the signals sent by the sympathetic nervous system, and stopped them from infiltrating the tumor and encouraging cancer spread.

OPEN ACCESS: The Sympathetic Nervous System Induces a Metastatic Switch in Primary Breast Cancer
[Cancer Research]
Metastasis to distant tissues is the chief driver of breast cancer-related mortality, but little is known about the systemic physiologic dynamics that regulate this process. To investigate the role of neuroendocrine activation in cancer progression, we used in vivo bioluminescence imaging to track the development of metastasis in an orthotopic mouse model of breast cancer. Stress-induced neuroendocrine activation had a negligible effect on growth of the primary tumor but induced a 30-fold increase in metastasis to distant tissues including the lymph nodes and lung. These effects were mediated by β-adrenergic signaling, which increased the infiltration of CD11b+F4/80+ macrophages into primary tumor parenchyma and thereby induced a prometastatic gene expression signature accompanied by indications of M2 macrophage differentiation. Pharmacologic activation of β-adrenergic signaling induced similar effects, and treatment of stressed animals with the β-antagonist propranolol reversed the stress-induced macrophage infiltration and inhibited tumor spread to distant tissues. The effects of stress on distant metastasis were also inhibited by in vivo macrophage suppression using the CSF-1 receptor kinase inhibitor GW2580. These findings identify activation of the sympathetic nervous system as a novel neural regulator of breast cancer metastasis and suggest new strategies for antimetastatic therapies that target the β-adrenergic induction of prometastatic gene expression in primary breast cancers.

[Lien]

Interesting. BTW this doesn't mean that occasional stress causes cancer to spread. It means that there is a possibility that long term stress could potentially cause metastasis. But many mechanisms that are seen in mouse models can't be reproduced in humans.

Another matter: people react differently to stress. Some produce large amounts of stress hormones, others don't. Some need just a few triggers to start the stress hormones piling up, others can tolerate lots of stress before they start producing adrenaline etc. So don't worry if you worry about your cancer. There's plenty you can do to get those pesky stress hormones down.
It won't do you any harm to do some mild exercises, enjoy a funny movie, have a massage, go to the sauna, meditate or do whatever you like to do to reduce stress. Laughing is good. Hugging is good. Having sex is good. Lying in the sun or walking on the beach is good.

So next time people accuse you of being lazy, tell them you are working very hard to keep the mets out of your system. Doctors orders!

Hugs

Jacqueline

[Rich66]

This is very interesting and I am compiling some bits on this. We are in an era where some of the cancer folklore is being validated by "science"..things like "Sugar feeds cancer"...well..maybe not directly but..kinda true.

This part did bug me though:

"We're going to be focusing on younger women, because they may have a multitude of things weighing on them when they're diagnosed with breast cancer. Younger women have more significant life demands and typically are under more stress," Ganz said.

Knock it off with the armchair psychology and get back to oncology..for everyone.

[Debbie L.]

Thank you, Rich, for the "bugging me" part. Me too.

(How do you do the quotes? I can't get it to work for me on this website although it does on others.)

While I wholeheartedly support recommendations that we work to improve our wellness with moderate eating of whole foods, exercise, and supportive spiritual practices, I am very wary of this kind of "research", when it's interpreted in a blame-the-victim kind of way.

We are individuals. We arrive in this world with different strengths (and weaknesses) and we are born into environments that affect us also (environments that are not within our control). To imply, even remotely, that how we deal with challenges in our lives has any affect on our health is to begin sliding down that slippery "blame-the-victim" slope.

I believe that we are each doing the best we are able, with what we are dealt. We can support each other, and encourage each other to explore what helps us -- and perhaps that will help us to move through the stresses. But simply to report that "stress is bad" does not help anyone. Stress is LIFE. As Jacqueline wisely said, we all have stress -- it's how we move through it, and how we adapt to our naturally-acquired responses to stress, that may make a difference.

I would submit that especially for those who are easily moved to anxiety, it causes MORE stress to be told that stress is bad. At the very least, research that reports these vague findings (IN MICE!), should note that findings in humans may be very different than in mice. It would be helpful also to acknowledge that suppression of normal responses, including anxiety, is not helpful. So many women I talk to firmly believe that the KEY to their survival after a cancer diagnosis depends upon that "positive attitude". To be held to that expectation is a tremendous stressor, in itself. We must each honor our own individual and innate responses, and work to find what best helps us to move through them -- not denying those responses but learning the tools that work (for each individual) to move away from angst and toward peace.

I think that it would be more helpful to present stress as an opportunity (rather than as a threat). Every life has stress. Most of us, although certainly stressed by our bc diagnosis, have other life-circumstances that are stressful, too. Many people without a cancer diagnosis have stresses much worse, much harder, than ours. Instead of saying "stress causes blank" (IN MICE!), it would be more helpful to talk of how each person can find ways that help them to move through stress (LIFE) -- to see challenges as opportunities for growth and stronger connections with others.

An alternative stress-free way of living would be to live in a protective bubble. We could construct the bubble with drugs or with isolation. But would that be living?

Sorry to ramble. This topic pushes some of my buttons (obviously, smile). I salute all who have the courage to acknowledge what's hard and who work to move through it.

Debbie Laxague

[Jackie07]

Well said, Debbie.

Let's see - I often talk about endorphene and how the 'happy hormone' can strengthen our immune system and bring better healing.

Do mice engage themselves in any 'happy' activities? Perhaps their 'exercise' help some...

My point is - human beings are so much more complex than mice in the aspect of our 'emotion' and decision-making processes.

Mice don't read books or locate information on the Internet. They don't have support groups allowing them to talk to others 'out of state' or around the world... I've never seen any mouse doctor itself or seek help from others.

However, I think we should take advantage of the research and get as much help/assistance from others as needed. Adequate rest, balanced meal, and happy mood definitely is needed for our cancer fight.

OK, Dr. Amen and other specialists are on CNN talking about the 'brain' right now. (Unlocing the mystery of the brain: how your thinking affects your quality of life)

ps.

"So next time people accuse you of being lazy, tell them you are working very hard to keep the mets out of your system. Doctors orders!"

Thanks, Jacqueline, exactly what I need to tell my family. Because they did not know about the huge tumor in the center of my brain, I was labelled as 'lazy' my whole life until I had the brain surgery when I was 30. [Then I became 'perfect'! ]I've had so many surgeries and worked very hard to keep different types of 'tumors' out of my system. My oncologist had just encouraged me to join the hospital's breast cancer support group to help newly diagnosed. I think I am going to encourage them to allow themselves to be 'lazy'...

[Adriana Mangus]

I DON'T KNOW what to believe.

My mother just passed away at 87 y/o. She was stressed out all her life, as the breadwinner of the family, she was in charge of 7 of us, 5 of us her children plus my aunt's 2 children. Yes, my mother raised them as well.

She would worked an average of 15 hours a day, 7 days a week. She did this for at least until she was 65+ y/o.

Now, the one thing she did right is to stay away from alcohol and cigarretes, other than that, I don't believe she had the best of a diet--black coffee in the morning with a pastry, light lunch-- and she would eat a big meal at night, mostly meat, potatoes and again--coffee.

Her heart wouldn't go any longer--the cause of death is listed as; having succumbed to a heart condition--in short, a vascular disease.

Is the stress different now than before? How does One differentiate the good stress from the bad strees?

Is stress necesarry in your life? What amount of stress?
How to cope with stress? Are we all different, yet so similar, that stress is a contributing factor to breast cancer for all type of women?

I have no answers. I have been stressed for periods of time in my life; divorce from my daughter's father, having to raise my daughter alone for years, highly stressful work environment for years and years. I also have worked since 17 years of age.

I'm the only one in the family with cancer. My oldest sister just turned 64, 9-15. She's healthy as a horse.

One day in the future there will be answers as to why some of us end up with cancer. Hopefully our children and grandchildren will benefit from these investigational researchs being done at UCLA and at the hospitals around the country and the world.

Just wanted to share.....

Adriana

[Lien]

A few observations:

Debbie: you are very right, telling people not to feel stress is a stressor. Besides, implicitly blaming people for their disease is a stressor as well. And people are not mice.
Rich: The same phrase worries me too. It's a stupid assumption.
Adriana: People react differently to stress and the production of stress hormones is a very individual thing.

There is one thing that is different now, that interests me. Research over the past ten or fifteen years has given us a lot more insight in the mechanisms of stress. We know more about its causes, the way it starts, the way it develops etc. MRI's have enabled us to see what happens in the brain and biochemistry has given us clues about the neurotransmitters, hormones and other substances that cruise through are bodies when we are stressed.

Because we understand these things better, we have developed more sophisticated ways of dealing with stress. Two techniques have shown great results with Post Traumatic Stress Syndrome: EMDR and PMA. They are able to eliminate or neutralize the triggers that cause an individual stress. These methods focus on subconscious patterns and work on a different level than traditional psychotherapy does.

The point is, that relaxation techniques don't eliminate the problem, they suppress the reaction we experience as stress. EMDR and PMA neutralize the triggers that cause the release of stress hormones. That's why meditation, exercise and other techniques bring temporary relief to some, but do nothing for others.

Another method I've been using on my kids, EFT, Emotional Freedom Techniques, seems to help as well. EFT uses acupuncture points on the face, upper body and hands and is easy to learn. I don't have a clue why and how it works, but I've seen some pretty impressive results.

In my practice as a business coach, I have been using PMA for 5 years now, and I've seen great benefits.

So if there's some truth in this line of thinking about cancer, we do not stand empty handed. That's why I think it's an interesting line of research. If we can develop a kind of therapy for those at risk, or those diagnosed with cancer, me might have an additional way of reducing the risk of cancer developing, spreading or recurring.

Again, this is very complex and stress reactions are highly individual. Something that is very stressful to one person is unimportant to another. Often there's a cumulative effect that's very hard to pinpoint. It's not something individual patients can handle easily. If it were, they wouldn't experience stress.

Jacqueline

[Ellie F]

Hi all
I have been really interested in reading all the comments and tend to agree in the main.One of the areas that interests me is whether childhood chronic stress may later result in a vulnerability to cancer. We know now that genes switch on and off and are not static as once thought. A number of years ago I attended a lecture by an American neurologist who believed that chronic childhood stress left a footprint in the cell memory which later got re-triggered if persistent adult stress happened. He speculated that this resulted in biochemical changes which may allow cancer to grow. Thought this was an interesting concept!

Ellie

[Rich66]

I remember someone posted a while back about visits to the forest being shown to improve outcomes.
The cool thing is now there is a basis for coverage of cruises, massages and other "relaxants". And survivors can always play the stress card when kids and spouses get on the ole nerves

[v-ness]

that part bugged me too! younger women have more stress? really? i don't think i am considered "younger" anymore at age 50 and the last couple years have been the most stressful i have ever endured. my father died in the garage of a massive heart attack or stroke in february 2006. my mom found him, and i was her closest support. in october 2006 my husband was diagnosed with stage 4 esophageal cancer with 3 large tumors in his liver. he died 10 weeks later. after him, 3 of our precious long-time companion cats died. then i was diagnosed with breast cancer in august 2009. i was convinced that the intense stress of the previous 3 years contributed somehow. my mom was incredibly stressed about the fact that she was unable to sell her home and had no idea what her future would be, then she was helping care for me, her eldest daughter. any mother knows how terrifying it is to have a kid with a life-threatening disease. then what happens? mom herself gets ovarian cancer during my treatment and died in june. death has tremendous impact on the survivors. i am convinced that all the stress of those deaths influenced bob's cancer, my cancer, and mom's cancer. so, back to my original point - the older we get, the more deaths we are faced with. i'm pretty sure losing your spouse at any age is a lot bigger stressor than, say, balancing kids and a job. it's pretty idiotic to focus on 'younger women' for the reasons they cite. and i'm pretty sure a larger percentage of 'older women' (how scientific a phrase) still get breast cancer more than 'younger women'.

WOW, DID THAT EVER STRESS ME OUT.

valerie

[Adriana Mangus]

Valerie,

Well said. I'm sorry about losing your husband..

Love,

Adriana

[Hopeful]

I posted a different type of stress study in the articles forum: http://her2support.org/vbulletin/sho...eferrerid=1173

This wasn't done in mice, it was done in a petri dish, however, what was learned is that stress, psychological or physical, induces a heat shock protein response in the body that protects tissues, and, since the protein is indiscriminate, it ends up protecting cancer cells as well as healthy cells. The biology is going to respond, even if the brain tells it not to.

Hopeful

[Lani]

Hopeful--see my new post today re stress/exercise and its timing. Also done in petri dish, but Hsp inhibitors have already shown promise fighting her2+ breast cancer in clinical trials, so biology probably similar.

[PinkGirl]

Oh crap ... now I have to worry about worrying. Any suggestion
of blaming the 'victim' drives me C R A Z Y ...

[karen z]

Lani,
Thanks for posting. The reality is that stress can not only hurt our bodies but it just doesn't feel that great subjectively. I went to my first meditation workshop yesterday, a kind of "meditation 101" if you will. LOVED IT. I am determined to find ways to quiet my mind and de-stress, for a lot of reasons! Also, taking painting!! I will let you know how it goes!!

[karen z]

Some interesting data on beta blockers appeared last March (see other threads). Pretty interesting if beta blockers can help.