Cancer-Enhancing Stress

Depression in post-op breast cancer patients can cause tumors to establish in bone.

By | July 17, 2012


Doctors and researchers have recently noted a trend that stress in treated breast cancer patients tends to correlate with a greater re-occurrence of cancer, which often spreads to the bones and lungs, and with higher rates of death. Now, new research published today (July 17) in PLoS Biology provides a mechanistic link between stress and metastasis: activation of the sympathetic nervous system in mice, a consequence of chronic stress and depression, is shown to promote the colonization of breast cancer cells in bone.

"[The authors] really beautifully put the whole picture together," said Laurie McCauley, who studies the hormonal controls of bone remodelling at the University of Michigan. In addition to demonstrating the involvement of the sympathetic nervous system, the researchers succeeded in reducing metastasis by blocking the effects of stress, pointing to new directions for drug therapies, though they note the immediate implication is regarding the importance of patients' mental health. "It's a very provocative and comprehensive study," said McCauley, who was not involved in the research.

Bone is constantly remodeled. Some of bone’s regenerative processes are regulated by hormones of the sympathetic nervous system, neurons of which extend into the bone marrow and the strong outer shell of bones, called cortical tissue. Hormones secreted by these neurons release cytokines that control the trafficking of cells generated in the bone marrow and the levels of osteoclasts and osteoblasts, which are involved in bone remodeling. The researchers found that changes in the bone microenvironment due to stress, which can increase cytokine levels , allowed metastatic breast cancer cells to colonize the bone more easily.

By introducing tagged human breast cancer cells to the blood of mice, the researcher were able to watch as the cells proliferated the bone when the sympathetic nervous system was activated, either by stressing the mice or using a drug that mimics stress. Colonization of metastatic cancer cells in the bone marrow was aided by the activity the cytokine RANKL, which promotes bone resorption.   Removing the receptor for RANKL in cancer cells blocked this migration in the mice.

"An increase in RANKL in the bone marrow environment promotes the migration of breast cancer cells towards ostebloasts," said study co-author Florent Elefteriou of Claude-Bernard University, France.

An antibody against this cytokine might then prevent the metastasis of cancer cells to bone, and in fact a drug (Denosumab) is already on the market which does this, and is currently used to prevent bone fracture. However, it is a very potent drug than inhibits the activity of osteoclasts, bone–resorpting cells, effectively freezing the bone remodelling process and increasing bone density. Another possibility is using a beta-blocker like propranolol to block the ß2 adrenergic receptor that binds to RANKL. Testing propranolol in the current study, the authors found that it significantly decreased the number of lesions and tumors observed in mice injected with human breast cancer cells.

However, while the study suggests two new drug routes to preventing the metastasis of breast cancer cells to bone, Elefteriou stresses the important implications for assuring breast cancer patients get the mental health care they need to stave off depression.

"We have a pharmacological approach, but I think we need strategies for reducing stress," said Elefteriou. "I know it's difficult when you have been diagnosed with cancer, but that may be another way to decrease sympathetic activation and avoid these stimulatory effects on metastasis to bone."

J. Campbell et al., "Stimulation of host bone marrow stromal cells by sympathetic nerves promotes breast cancer bone metastasis in mice," PLoS Biology, 10: e1001363, 2012.


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Avatar of: leighmac68


Posts: 1

July 18, 2012

Florent Elefteriou is the director of the Vanderbilt Center for Bone Biology. He and all of the authors of the PLoS Biology study are at Vanderbilt University.

Avatar of: TheSciAdmin


Posts: 56

July 18, 2012

Thanks for pointing that out: it has been fixed now.
- Hayley Dunning

Avatar of: Avoided Cranium

Avoided Cranium

Posts: 1

July 18, 2012

Stress or depression? Which is it? The terms are used interchangeably, but they are completely different things.

Avatar of: vckkpts


Posts: 1

July 19, 2012

You cannot have depression without stress an anxiety. Anyone who is a psychotherapist will tell you that. I am. All mental health illnesses involve a certain amount of stress.  Stress being defined as an inbalance in the homeostasis of the organism.  Anyway this report is only validating empirically what Eastern philosophy has been saying for thousands of years.  ho hum

Avatar of: ICHHA PURAK


Posts: 9

July 19, 2012

Attempts should be made to reduce stress in the patient,though it is a difficult route.Along with that cytokine levels should be controlled by means of drugs to prevent mteastasis

Avatar of: azar123


Posts: 11

July 19, 2012


This is study is meaningless and completely artificial.  Cells were injected intracardiacly and bone
metastasis were allowed to be established. No attempt was done to try to inject
cells into the mammary fat pad and see if indeed they metastasize to the bone.
Any conclusion drawn from this  artificial
mouse model whereby human cells  grow in
mice on human stress and cancer metastases is completely and utterly irrelevant
to the human situation and is preposterous!!!

Avatar of: Reyna Favis

Reyna Favis

Posts: 1

August 17, 2012

The study is not meaningless or artificial. Post operative breast cancer patients in general lack breast tissue. Injecting tagged cells into the mouse mammary fat pad makes no sense given this reality. Circulating cells with metastatic potential that may be below the limits of detection for conventional cancer marker tests are a major worry for breast cancer survivors. These are the cells that could take advantage of RANKL-mediated bone remodeling and form a bone metastasis.
Given the results of this study, another potential problem for breast cancer survivors is that SSRI inhibitors to treat depression are contraindicated for those taking tamoxifen.

September 14, 2012

Any mouse model is just that - a model. That doesn't take a way from the importance of the study or the significance of its findings. If you did the medical research using mice yourself, you'd know that tumors dod not metastasize in mice they way they do in people.

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