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Insights Into Cancer – February 10, 2015

Stress and Cancer: Myths, Evidence

Presented by Steve Cole, PhD

About the Lecture

How does stress affect cancer? And what can we do about it? This talk provides an update on what we’ve learned over the last decade in medical and laboratory research on stress and cancer. Some common ideas turn out to be myths (stress generally does NOT cause cancer). Others appear to be true (stress CAN make existing cancers more aggressive). Many stress effects on cancer are driven by fight-or-flight responses that active “defense programs” in the human genome and inadvertently promote the spread of cancer. The good news: several behavioral interventions and wellness practices have been shown to de-activate these genomic defense programs. Drugs once used for heart disease can block neural stress signaling to cancer cells and the immune system. And strong social networks and deep personal relationships play a key role in helping our bodies run well. At the end of this talk, you’ll be up-to-date on the physiological links between stress and cancer. And most importantly, you’ll know what YOU can do to help protect health in a world where stress is inevitable, but we have more choices than ever in how we respond to it.

About the Speaker

Cole - F4E5 v3Steve Cole, PhD is a Professor of Medicine in the Division of Hematology-Oncology at the UCLA School of Medicine, and one of the world’s foremost experts on the molecular pathways through which social conditions, psychological processes, and the nervous system influence the human genome and cancer biology. His research on breast and ovarian cancer is supported by the National Cancer Institute, the National Institute on Aging, and the Breast Cancer Research Foundation.

Lecture Summary

In 200 AD, over 1800 years ago, Galen of Pergamum, the renowned physician who is referred to as the “father of experimental physiology, “ observed individuals who developed cancer and came to the conclusion that the characteristics of the person were related to the development of cancer. Specifically, he concluded certain personality traits, such as melancholy and hopelessness, were factors that gave rise to cancer. While there was little empirical data to support this, the idea of a “cancer-prone personality” has persisted and the idea has broadened into a popular belief that stress might cause cancer. Along with these ideas came an attitude that the way we live our lives can create certain vulnerabilities to illness and that individuals with harder lives may have poorer health. From these notions, two pressing lifestyle questions emerged. Only in the last ten years have we had enough data to give real answers to these questions.

Does Stress Cause Cancer?
The data do not support this as fact; this is a myth. In fact, we now know that cancer develops over time and, for the most part, many adult cancers are related to living a longer time. Cancer is predominately an acquired genetic disorder that stems from the normal process of DNA damage and DNA replication that goes awry. It goes awry because, over time, the DNA replication process—a very robust process with many checks, balances, and correction mechanisms—develops errors, or “dings” over time. As these “dings” accumulate, they eventually lead to mistakes that start out small, but in time change how the DNA of a cell functions, leaving it without all of the characteristics of its original cell and with the characteristics of a cancer cell. Some of the special characteristics that cancer cells acquire are: (1) cancer cells stimulate their own growth; (2) unlike normal cells, they resist inhibitory signals that might otherwise stop their growth; (3) they resist their own programmed cell death, called apoptosis; (4) they stimulate the growth of blood vessels to supply nutrients to tumors, called angiogenesis; (5) they can multiply forever; and (6) they can metastasize or invade local tissue and spread to distant sites. There is little consistent evidence from either biological studies of cancer cells or epidemiologic studies of cancer rates in humans that stress significantly contributes to the accumulation of DNA damage that fundamentally “causes” cancer.

If Stress does not cause Cancer, then Stress must not matter?
This is also a myth; stress does matter, but it affects primarily the progression of established cancers. Research into cell biology and the immune system, have taught us a lot in the last two decades. There appears to be a biological consequence of how people respond to stress (behaviorally and chemically) that may have implications not for whether they get cancer, but potentially for how their cancer might metastasize and grow. This may account for some small amount of the variance in cancer progression rates over time, although not all by a long shot. Nevertheless, it is an interesting correlation, one which may provide opportunities for helpful interventions to at least a subset of individuals who confront significant levels of stress. The science is young, and we need to do more research, so the information below is an introduction to a highly complex system. It is important to note, this lecture does not imply that an individual has to have a positive attitude about their cancer or should not express their feelings about their cancer! There is no tyranny of positivity here! After all, forced positivity can itself be stressful, particularly when confronting a situation as threatening as cancer.

Understanding more about Cancer
In simplistic terms, there are two general phases to the biology of cancer (called “incidence” and “progression” by researchers). The first part is “presence” of the cancer, or how it gets initiated. The second part is the “speed” or the progression of the cancer once it has been initiated. The actual initial primary tumor (presence) is generally not what makes cancer life-threatening; it is when cells from the primary tumor metastasize (progress) beyond its initial site and spread to other organs that it becomes most threatening to physiologic function and survival. Before it spreads, cancer can often be surgically removed but if it has already left the original site and metastasizes to other vital organs it becomes much harder to treat and of much greater concern.

In fact, the molecular and cellular process of developing cancer takes years, sometimes decades for some cancers. It begins with a normal cell in which some small aberration occurs. Over time, as more aberrations accumulate, and lead to progressively greater changes in cellular function, the abnormal cells develop from pre-cancerous to carcinoma in situ, a fully contained tumor composed of many abnormal cells. Finally, as these cells become more mutated they often gain new mobility and survival capacities, and they use the blood cells like a highway to travel through the body and establish colonies in other parts of the body. These new growths are called metastases.

Over the last decade researchers have been able to study human cancer cells in mice that have been altered to have no immune system. This research has led to a much better understanding of human cancer and its processes. A tumor placed in a body does not tend to spread, but the interaction of the tumor with the signals and chemicals produced by the surrounding tissue and other physiological systems may conspire, so to speak, to help the cancer cells survive and metastasize. We now know that the microenvironment around the cancer cell, as well as the macroenvironment of the body, has a great influence on what happens to these initiated cancer cells. In the microenvironment, the cancer communicates with other cells. In particular it sends signals that it needs a blood supply, and vessels begin grow to support and feed the tumor that also provides a “superhighway” to carry cells to other parts of the body. Further, our immune cells may not see the cancer cell as a foreign body, because it originated as part of our body. Instead, the immune cells see it as a part of the body that is broken and needs healing. The immune cells then mount an inflammatory response which creates proteins that inadvertently help speed the growth of the tumor cells. The macroenvironment consists of signals from a higher level in the brain that coordinate hormones and neurotransmitters that influence virtually all aspects of our physiology. It is at this level that some of these signals help promote the growth and metastasis of cancer. Research shows that biological responses to stress have much greater effects on the biological processes driving tumor progression and metastasis than they have on the biological processes (e.g., DNA damage and repair) that initiate the primary tumor.

Understanding the Stress Response
Many of you have heard of the human body’s “fight or flight” response. The fight or flight response is an innate physiological reaction carried out by the sympathetic nervous system that prepares the body to flee or fight in dangerous situations. This response was developed to respond to perceived harmful events, attacks, or threats to our survival—acute responses that were programmed survival responses needed by our ancestors. The fight-or-flight response helps the heart pump more blood, prepares the muscles to respond; it affects most organs in the body including the circulatory system that distributes our immune cells and the bone marrow, the birth place of our immune cells. Under acute stress, the brain triggers the release of hormones and neurotransmitters, and it is these biochemical signals that stimulate specific pre-programmed biological reactions in various types of cells throughout our bodies. These systems originated to help defend us against physical threats and injuries, but in our more modern world, they are most often activated by psychological and social stresses that occur daily. Interestingly, the same innate response is triggered by these psychological and social stressors. We get the same physiological response to psychological and social stressors and signals processed in the brain trigger the release of stress neurotransmitters such as norepinephrine and stress hormones such as epinephrine and cortisol. If these stressors remain chronic, the repeated or chronic low-level activation of these biochemical signaling pathways can alter the expression of immune-related genes that circulate in white blood cells. One stress-response “program” that is wired into our genome involves ramping up inflammatory response to help respond to potential injury. However, when activated over long periods of time (months to years), this inflammatory response can influence disease susceptibility, such as an increased susceptibility to a variety of chronic illnesses including cardiovascular and neurodegenerative diseases.

The big question for cancer is whether this chronic inflammatory response cycle that gets set off by chronic stress has any impact on cancer. One of the ways this has been studied is through epidemiologic research of large groups of individuals with some interesting findings. The data do not suggest that the chronic inflammatory response significantly affects the initial development of cancer (initiation). However, there is some evidence that stress and inflammation may influence the rate of progression and metastasis of established cancers. One might hypothesize that individuals who have high stress from a lot of life adversity might not survive as long as those with less adversity. In fact, when 3.2 million US adult cancer cases (that included all types of cancer and all stages) were examined and the average five-year survival rates were compared, they found that the people who live in poverty had a 6% lower average survival rate. On the other hand, the more affluent patients had about a 3-4% higher average survival rate. This is about a 10% spread. Using this same data, it was found that those who were married, regardless of the quality of the marriage, had a 5% higher average survival rate (we saw a slightly greater benefit for men than women), while those who had recently separated (the most stressed of the group) had an average survival rate that was about 5% lower (again, an approximate 10% difference in survival rates). There were similar socially-related survival advantages across age groups and ethnic status. Interestingly, when the types of cancer were also graphed, these social differences were quite similar across most types of cancer and, more importantly, held similarly in cancers that were known to be really bad, aggressive cancers as well as those that were known to be less aggressive. It raises an interesting question about how do people really get that 10% advantage and how do stress and social support affect cancer progression?

The Study of Stress and Cancer Progression
We are in a new era studying the relationship between stress and cancer. It appears that most blood vessels have nerve fibers around them. When a tumor signals the blood vessels to send a blood supply, it turns out that the nerve fibers also come along for the ride and begin signaling and sending biochemical messages.

As I noted earlier, mouse models have revolutionized our ability to understand cancer and also to test the impact of medications and physiological influences on cancer. In recent studies, mice without immune systems had (initiated) breast cancer cells injected into their breast tissue. Some of these tumor-initiated animals, the control group, were allowed to roam freely in their housing environment; mice like to run free. Others in the experimental group were stressed by putting them in a small box for a couple hours a day. They were not traumatized or tortured, just confined, a bit like putting someone in a coach plane seat for a number of hours. Mice really don’t like that kind of confinement, and they showed significant fight-or-flight stress responses as a result. The researchers were able to assess how the initiated tumors grew and metastasized and the results were dramatic. The control mice had very little or no metastatic disease, but the stressed mice developed multiple metastatic tumors over the course of a month. In both groups, the primary tumor showed the same rate of growth, but the locally confined “disease” progressed much more extensively in the confinement stress group. What this implies is that, in mice, stress promotes the progression of the metastatic disease, but it does not affect the primary tumor. This same experiement was repeated using leukemia, ovarian cancer, prostate cancer, pancreatic cancer, and a diverse array of other tumor types as well.

Of course it is not possible to conduct these experiments in humans, but one way that researchers can assess the same issues in humans is by looking at arrays of gene panels and identifying which genes are turned on and off in patients and under which conditions. In addition, they can be studied in patients with high and low social support. What is seen at the molecular level in cancer tissues from human patients with low social support looks quite similar to what is seen in the tumor tissues of mice in these experimental stress studies.

We have come to understand more about how the inflammatory response by the immune system may actually promote cancer progression. The tumor cells start damaging the neighboring cells as they grow and, as a result, these neighboring normal cells send signals to the immune system to come deal with this problem and repair what the body interprets as a wound. The immune system cells, unfortunately, do not recognize the cancer cells as being different, and so the immune system activates inflammation and tissue remodeling to repair the “wound.” They do that in a couple of ways that actually favor the cancer. For one thing, there is a matrix of proteins that keeps cells arranged in an orderly fashion, and functions like a seat belt keeping them in place. When the immune system gets in there and starts trying to fix the wound, it breaks up the matrix proteins, which essentially releases the seat belt that restrains the tumor cells. In doing this, the cancer cells are now untethered and are free to roam. The new blood vessels that were also recruited to feed the tumor can now serve as a super highway for the cancer cells to escape into other parts of the body. While many will die in the process, some will survive and will establish colonies other organs and produce metastases. When we are under stress, we make more of the immune cells and inflammatory molecules that generate metastasis tumor progression.

Let’s go back to the mouse model. Researchers were able to observe that when the biological stress response was blocked using “beta blocker” drugs, the immune system stopped producing such vigorous inflammatory reactions in the primary tumor, and the rate of metastasis was greatly reduced in stresseed mice (no different from the non-stressed control mice). The primary tumor still grew larger in the stressed mice, but the rate of metastasis was greatly reduced using a drug to block the biological stress signal.

The next question that arises from this research model is what we do about these stress effects on cancer progression in humans. In the mouse model, specific beta blocker drugs were helpful and the use of drugs to dampen the immune system’s ability to “listening to the stress response” is one approach that is under investigation.

There is some evidence that old beta blockers may block the stress response better than newer ones, but this protocol is still under early stage investigation and is not ready for use in humans. It needs more empirical research to make sure there are no unintended consquences or side-effects.

What else might be useful besides drugs? There are a variety of psychological studies that have been successful in reducing the stress response in humans, and have shown positive impacts in reducing the molecular processes involved in inflammation. These techniques include cognitive behavioral interventions, mindfulness, teaching a relaxation response and mindfulness, yogic meditation, yoga and Tai Chi. These techniques appear to block the perception of stress at the higher brain levels and thus reduce fight-or-flight signaling to the immune system. Many of these same studies also show improvements in coping, quality of life, and reductions in anxiety and depression. Many of these services are offered through the Simms/Mann—UCLA Center for Integrative Oncology.

Interestingly, a third option appears to be “dedication to making the world a better place.” People who focus on a cause or purpose greater than their own immediate happiness or self-grantification, who are dedicated to advancing a cause, pursuing a significant long-term goal, or are committed to greater good, also tend to have more favorable profiles of molecular activity in their immune cells (including reductions in inflammatory signaling). This focus on a higher purpose in life beyond simple immediate happiness is known as “eudaimonic well-being,” and is often measured in research by the extent to which people report “life has direction and meaning, or I am actively working to be a better person.” The other side of eudaimonic is “hedonic,” which is the kind of well-being that derives more from personal happiness and satisfaction. People with relatively high levels of hedonic well-being but low levels of eudaimonic well-being showed comparatively unfavorable profiles of inflammatory gene expression. While both types of well-being are associated with similar levels of positive emotion, they appear to have different correlates at the cellular and molecular level. We do not yet know whether this is really something that can be shifted or not, but it raises interesting questions for additional research.

We also know that individuals who are more integrated with others have a more favorable gene expression as compared to individuals who are isolated and lonely. The activation of the caregiving and nurturance response may play a role in reducing stress response in the brain.

Take Away Message
There is obviously much more research to be done, and lots of it is in process. Below is a brief summary of what we know as of today:

  • Stress does NOT cause cancer. Being alive a long time, and the inevitable wear and tear on our cells and DNA is the general cause of cancer.
  • We have evolved a culture where just about everyone is stressed, and how can you not be stressed when you have cancer?
  • The epidemiological data shows that what is most important for cancer at the psychological level is the amount social support one has to help manage the inevitable stress of life and the extra stress of cancer.
  • The good news is that 70-80% of us have high levels of social support and we will do as well as we can.
  • For the other 20-30%, we know how to identify those individuals who are at risk, and we are learning more about what we can do to protect against the adverse biological effects of high stress cultures in the context of low social support including:
    • Cognitive-behavioral stress management
    • Meditation
    • Possibly beta blocker medications in the future
[Editor’s Note: The Simms/Mann – UCLA Center for Integrative Oncology offers a range of psychosocial support services ranging from individual support, cognitive behavioral interventions, groups that train patients in mindfulness, Qi Gong, and the relaxation response. We cannot promise these tools will help limit your cancer progression but we know from a vast evidenced-based body of research that mind/body interventions make a difference in the way people experience their cancer journey, reduce distress and help improve quality of life and well-being. Finally, for those of you with an eudaimonic orientation, all these services are offered without fees. We are 100% donor supported and depend on your willingness to get involved to support the Center so that these services are available for the next person and family touched by a cancer diagnosis. Please donate! Join us in our quest to ensure our services are available for everyone, until cancer is wiped from the face of the earth.]

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