Insult Becoming Injury Stress and Metastases
Abstract & Commentary
By Russell H. Greenfield, MD, Editor
Synopsis: A murine model was employed to assess the effects of chronic stress on metastatic breast cancer spread. The researchers used a variety of tools to investigate the neuroendocrine, molecular, and cellular effects of chronic stress in this setting. Their findings suggest that chronic stress induces a significant increase in the extent of cancer spread through the activity of the sympathetic nervous system. The findings open numerous research questions yet to be answered, as well as great therapeutic possibilities.
Source: Sloan EK, et al. The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res 2010;70:7042-7052.
The impact of chronic psychosocial stress on immune system function has been the focus of many studies, the results of which largely suggest an associated impairment of various immune compartments. Fewer studies have been performed that specifically address the impact of stress on immune activity and cancer. The data regarding an association between stress and the initial development of breast cancer, for example, are inconsistent, while other studies have specifically linked an increased spread of cancer to stress. The authors of this animal study looked at the effect of chronic stress on the distant metastatic spread of primary breast cancer.
Six-week old female mice, some with an intact immune system and others bred to be T cell deficient, were injected with 66c14 mammary adenocarcinoma cells into the 4th mammary fat pad for spontaneous metastasis studies, or into the tail vein for organ colonization studies. The frequency and quantity of metastases were tracked in live mice through repeated use of a non-invasive optical imaging process that can resolve as few as 3,000 cells. In addition, mice under anesthesia were photographed and metastases measured by triplicate determination of bioluminescence in a region distant from the primary tumor (primarily the chest region and focusing on the lung, and axillary and brachial lymph nodes). Tissue-specific metastases were measured ex vivo by bioluminescence immediately after sacrifice on day 28, or by microscopic evaluation on day 41 in experiments involving prior removal of the primary tumor.
Mice were randomly assigned to home cage control conditions or to 2 hours of restraint per day for 20 days that began 5 days before tumor cell inoculation, or for a period of 14 days beginning 2 days after surgical removal of the primary tumor. Restraint consisted of being placed in a confined space that prevented the mice from moving freely, but that did not press on them or induce physical injury or pain. This method has reportedly been shown to induce a state of chronic stress as demonstrated by neuroendocrine activation (increases in circulating catecholaminergic neurotransmitters and corticosterone levels), weight loss, and anxiety-like behaviors.
Mice received isoproterenol at a receptor-saturating dose by daily s.c. injection commencing 5 days before tumor inoculation to study the effects of beta-adrenergic agonism. For beta-adrenergic antagonist studies, two days before commencing stress or control conditions mice were implanted with a 21-day release pellet containing either propranolol, in a dose sufficient to block peripheral beta-adrenergic receptors, or placebo. Additional studies included determination of cAMP synthesis, analysis of macrophage infiltration and vascular density, and expression of metastasis-related genes.
Results showed metastatic spread of disease in both the stressed and control mice. Noninvasive imaging in control mice revealed a progressive increase in the spread of tumor cells to lung and chest lymph nodes that plateaued 21 days after tumor cell inoculation; however, chronic stress increased the metastatic spread of primary breast tumor cells to distant tissues 38-fold vs. controls (P = 0.04). Stress increased metastasis in the lung 37-fold (P = 0.034) and 67% in the chest lymph nodes (P = 0.009). Increases occurred in both the number and size of metastatic masses. Notably, primary tumor growth rate was not impacted significantly by stress, but there was an associated increase in the expression of proinflammatory and prometastatic genes within the primary tumor.
When tumor cells were injected directly into the bloodstream and bioluminescent assays of distant tissue tumor signals were performed, a 3.3-fold increase in distant colonization rates as a function of stress was found. Ex vivo analyses of tissue harvested 27 days after injection found that chronic stress increased lung tumor colonization 2.5-fold (P = 0.038) and lymph node colonization 2.1-fold (P = 0.037). In another experiment, restraint was initiated only after surgical removal of the primary tumor to examine the effects of stress on metastases independent of effects on the primary tumor. Results showed that stress increased metastatic spread 2.7-fold (P = 0.05).
When unstressed mice were administered the beta- agonist isoproterenol, metastatic spread to distant tissues increased 22-fold compared with saline-treated controls (P = 0.03). Treatment with the beta-blocker propranolol had no significant effect on metastatic burden in control mice (P = 0.08); however, propranolol completely blocked stress-induced metastatic spread in the mice subjected to chronic restraint (P < 0.0001). Propranolol had no effect on primary tumor growth in the mammary fat pad in either group. Additional investigation showed that T cells were not associated with the immune impact of chronic stress, but that there was a stress-induced recruitment of immune cells, specifically macrophages, that was blocked with administration of propranolol.
The study authors state their findings identify sympathetic nervous system activity as playing an important role as a physiologic regulator of breast cancer metastasis to lymph nodes and lung in both immunocompetent and T cell deficient mice through beta-adrenergic signaling. As a downstream result, activated macrophages are recruited to the primary tumor site and there is an increase in prometastatic gene expression.
Commentary
It is puzzling that research showing how chronic stress can mediate the risk of metastatic breast cancer spread has not found a wider audience in the lay press. This should be big news, and promising news, coming out of a well-done study protocol. Yes, these are animal data, but they help solidify a hypothesis in humans where exploration has already begun.
Conventional medical studies have suggested that employing beta-blockade might lessen the risk for metastases in the setting of cancer. CAM, and some conventional, trials have highlighted findings suggesting a myriad of benefits from stress management in the setting of cancer, but few if any have explored the neuroendocrine impacts of psychosocial tension.
Stress induces the release of norepinephrine into both the local microenvironment and systemic circulation. As the authors note, nerve fibers from the sympathetic nervous system are present in organs that serve as prime targets for breast cancer metastasis, including lymph nodes, lung, and bone. The new findings suggest that the effects of the autonomic nervous system extend even to poorly innervated structures, including solid tumors.
This article raises many questions, starting with a significant ethical oneshould animals be subjected to this type of treatment in the name of human medical science? Alternative Medicine Alert is not the proper forum for this discussion, but one would be hard-pressed to read this study and not come away with the question.
On the other hand, there are findings from this study that have real and actionable impact, at least in the form of generating new research questions such as: should all women with breast cancer be placed on low-dose beta-blocker therapy? Can beta-blocker therapy be of benefit in other forms of cancer treatment? Would stress management techniques such as meditation, exercise, and massage therapy have benefit with respect to limiting the spread of metastatic disease by quelling the degree of neuroendocrine activation in an inherently stressful situation like the diagnosis of cancer? Is there reason to combine beta-blocker therapy and specific stress management therapy for people with breast cancer? If stress management techniques are of benefit in this manner, are they all of equivalent effectiveness?
These findings are truly excitingthey bring hope to all who are touched by cancer; they raise new prospects for ways that people might lessen their risk for metastatic spread of cancer simply by improving lifestyle habits (stress management); and they point out that select CAM therapies have hard conventional bench data supporting their potential clinical use. We await human data that parallels this study's findings, but how good to be able to tell our patients that engaging in stress management practices upon receiving a diagnosis of breast cancer, if not other tumors, may not only help them feel better but might also help limit spread of the disease.
A murine model was employed to assess the effects of chronic stress on metastatic breast cancer spread. The researchers used a variety of tools to investigate the neuroendocrine, molecular, and cellular effects of chronic stress in this setting. Their findings suggest that chronic stress induces a significant increase in the extent of cancer spread through the activity of the sympathetic nervous system. The findings open numerous research questions yet to be answered, as well as great therapeutic possibilities.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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