Can Excess Stress Cause Cancer?

As discussed in the last post, Caveman Doctor was recently asked if stress caused cancer by Cristina.  Before Caveman Doctor answered this question, he felt it was necessary to tackle the general topic of stress and its damage on the body.  Caveman Doctor also just tackled cooking an entire wild duck breast, ate it all, it was delicious and he is more than ready to also tackle the topic of stress and cancer.  There is a lot of tackling going on today for Caveman Doctor.

 

Sedona breakdance Can Excess Stress Cause Cancer?

Break-dancing on Devil’s Bridge: stress reliever for me, but stress-causer for everyone watching…

 

Stress, Cancer, and the Inflammatory Glue that Keeps them Together

While we don’t have conclusive, high-level evidence to answer the question of “Does stress cause cancer?” due to ethical issues as this would necessitate a clinical trial that in essence would give its participants high amounts of stress and then analyzing their cancer rates (though to a degree this is happening every day), the data is very convincing that the two are intimately linked, though not as intimately linked as the succulent flavor of duck fat and the duck meat that Caveman Doctor just finished eating.
 
From the last post on stress, we know that stress, more so chronic than acute, causes the release of inflammatory cytokines and damage to our normal tissues.  The real question still remains: Does stress cause cancer?
 
To address this question, we have to go far back in time to 400 BC, when Caveman Doctor was about 2.3 million years old and humans were about 8,000 years into eating a new diet that their bodies were incapable of handling.  At this point, Hippocrates, one of the earliest documented physicians, began treating patients with willow tree bark to help their symptoms of pain and fever1.  While Hippocrates may not have realized it, he was actually treating these patients’ inflammatory symptoms with aspirin, which is found in the bark of the willow tree.  Fast-forwarding 2400 years, we are still prescribing a plethora of medications for inflammation, including aspirin, while we can likely avoid it in the first place by eating a caveman diet and mimicking a modern caveman lifestyle.  However, through treating inflammation and inflammatory diseases our knowledge of their connection with cancer has grown considerably, as you will read below.
 
 

Stress = Inflammation = Cancer?

This may never be proven conclusively in our lifetime, but the connections are so incredibly close that it is difficult to deny the relationship.  Several diseases that are defined by chronic inflammation result in significantly increased risks of cancer, such as colon cancer in patients with ulcerative colitis (an inflammatory bowel disease)2,3.  Interestingly, studies show that irritable bowel disease in itself can invoke stress, and as a result, decrease immune function4.  Animal studies have shown that stress alone can exacerbate colitis5, connecting the two (which comes first?).  Also, many of the inflammatory conditions that often lead to cancer include auto-immune diseases (the body attacking itself) which we know is one of the results of chronic stress and inflammation.  Other scientific data quote one in five cancers results from inflammation, and extrapolating from the studies on stress, it would not be unreasonable to assume this would include stress-induced inflammation.  Another more common example is cigarette smoke, which causes chronic inflammation in the lungs, producing oxidation (and free-radicals) and leads to DNA damage and chronic obstructive pulmonary disease as well as lung cancer6.  A hallmark of both of these processes in the activation of nuclear factor-Kappa B (NF-KB), which is a protein complex that the body produces in response to inflammation, free radicals, cytokines, all hallmarks of stress.  Of note, deregulation of NF-KB has been found in many human cancers7 and increased NF-KB activity has been associated with breast cancer8.
 
Interestingly, when we surgically resect precancerous lesions, which are basically growths of cells that are not quite cancer but are definitely not normal, they most often contain the immune cells and cytokines that we know stress can increase.  These inflammatory cytokines have also been shown to cause cancer to spread (metastasize) to other organs9, result in further inflammation, and even cause tumors to increase their blood supply (angiogenesis)10.  This in itself creates somewhat of a (free-range pastured) chicken versus the egg argument in terms of whether inflammation causes cancer or cancer causes inflammation.  When reviewing all the data it appears likely that the answer is both are true.
 
Epidemiologic data, acknowledging all of its shortcomings, has revealed that chronic inflammation correlates with tumor progression in patients already with cancer11.  C-reactive protein (CRP), tumor necrosis factor (TNF), and IL-6, all cytokines known to be increased from stress, are also increased in cancer patients12,13.
 
 

But Does Stress Cause Cancer?

Epidemiologic data has shown that chronic depression, stress, and lack of social support are all risk factors for cancer14A study in humans even showed chronic depression and even the death of a mother during childhood to be associated with increased breast cancer in women15.  While we do not have concrete evidence in humans, animal studies more definitively point to stress as a cause of cancer.  Just like the mice that had an increase in their inflammatory cytokines from social stress in the last post, another study took mice prone to skin cancer and gave them artificial sun exposure for 10 weeks.  Half of the mice were chronically stressed and half were not.  The chronically stressed mice had decreased immune function and experienced tumor development significantly earlier than the non-stressed mice16.  Other mouse studies of ovarian cancer showed that chronic stress resulted in increased cancer growth as well as increased angiogenesis, the process with which cancer forms new blood vessels to feed itself nutrients for growth and metastases17.
 
Chronic stress has also been shown to decrease our body’s ability to mount an attack against foreign invaders, including viruses18.  As we know that several viruses can cause cancer (HPV and cervical cancer, and EBV and nasopharyngeal cancer), we can extrapolate that any decrease in immune function could increase cancer risk.  Interestingly and conversely, studies show that mindfulness meditation, a form of stress alleviation, actually stimulates the immune system, resulting in increased ability to fight viral pathogens, and potentially fight cancer19.
 
 

Stress and Blood Glucose

The other main issue, as discussed in my previous stress post, is the cortisol release from stress.  Cortisol causes the level of glucose in the blood to rise, and if this occurs too frequently, could lead to chronically elevated levels of blood glucose (a state similar to diabetes, which in itself may lead to cancer20,21).  In fact, stress can raise blood glucose levels to double their normal amount22.  Depression, a common form of chronic stress, causes hyperactive responses to stress and a chronically elevated levels of cortisol, which undoubtedly will lead to a chronically elevated level of blood sugar23.  We already know that cancer cells are fueled by glucose and people with higher serum glucose levels have an increased risk of cancer24.  One of the main goals of a caveman diet is to minimize any spikes in blood glucose levels and to keep them chronically low.  Chronic stress works counter to this goal and any way to minimize it would be beneficial.
 
 

Can Stress Actually Help Fight Cancer?

Similar to the mouse study above, another group looked at skin tumors (squamous cell carcinoma) in a group of mice prone to such cancers, to see if acute stress could modify this.  One group of mice was restrained for 2.5 hours 3 times per week, causing acute stress for the animals.  Afterwards, they were exposed to ultraviolet light.  Another group did not undergo the stress before light exposure25.   The acutely stressed group actually had greater numbers of activated T cells, lower cancer incidence and fewer numbers of skin tumors.
 
However, other studies in mice with breast cancer show that once cancer has already been initiated, stress can lead to increased rates of tumor spread and metastases26.  Similarly, when mice were injected with leukemic cells and stressed physically and physiologically with injections of adrenaline, cancer progression occurred27.  Some scientists even propose that, while necessary in many cases of cancer, undergoing surgery may cause enough stress to lead to tumor promotion and progression28.  Therefore, it seems like acute stress may help fight cancer, chronic stress may help cause it, but once cancer is present, both acute and chronic stress may lead to cancer progression.
 
 

Putting Your Money Where Your Stress Is

However, if stress and the inflammation that it causes do not lead to cancer, one would have to wonder why the billion dollar pharmaceutical companies are betting on the relationship.  In fact, medicines that combat the inflammatory mediators released from stress, such as TNF and IL-6, are currently in clinical trials for the treatment of cancer29.  Once again, we don’t have proof that stress causes cancer, but big pharma is putting their money where their mouth is and targeting the same inflammatory mediators that stress causes in order to treat cancer.  In fact, we already know that some medicines that decrease inflammation can reduce the risk of cancer and this was actually what they were trying to accomplish with Vioxx before the infamous mega lawsuit happened30,31.
 
 

In Conclusion:

Stress, especially chronic, likely causes cancer and if I were a betting man, I would bet the cave on it.  Acute stress, assuming that it is not great enough to cause a heart attack or physical trauma, may actually protect against cancer as it stimulates our immune system.  While these conclusions are based on a lot of epidemiologic data, associations, and animal studies, the data is relatively strong.
 
 

Some parting thoughts:

  1. Stress (chronic more so than acute) leads to inflammation.
  2. Acute stress may boost your immune system to help fight cancer.
  3. Chronic stress may weaken our immunity and even lead to cancer.
  4. Cancer and chronic inflammation are intimately linked.
  5. Once cancer is diagnosed, any stress may result in increased aggressiveness of the cancer, but the data is minimal.

A caveman’s life was likely defined as a series of periods of downtime and non-stressful relaxation with little to do, speckled with periods of acute stresses where he was building a hut and lifting heavy stones, running from a bear, or jumping in a freezing cold lake.  While in a more primordial state of survival mode, the caveman likely avoided many of the chronic stresses that plague modern man as they were irrelevant.  Needless to say, it’s likely the caveman encountered some chronic stresses as well (like which bear skin loin cloth made him look best for cavelady).  Lucky for him, nature gave him the optimal diet and exercise regimen to conquer the ensuing inflammation.  To be your healthiest and to optimize your body’s ability to ward off infections and cancers:

  1. Minimize chronic stress.
  2. Engage in some acute stresses and challenges like lifting heavy weights or running sprints (not marathons, and not necessarily from a bear), or mental challenges and new experiences.
  3.  Eat like a caveman to give your body the antioxidant and anti-inflammatory fuel it craves to repair itself (the food Nature provided for us).

 

References:

1. Rainsford KD: Anti-Inflammatory Drugs in the 21st Century
Inflammation in the Pathogenesis of Chronic Diseases, in Harris RE, Bittman R, Dasgupta D, et al (eds). Subcellular Biochemistry, Springer Netherlands, 2007, pp 3-27
2. Ekbom A, Helmick C, Zack M, et al: Ulcerative Colitis and Colorectal Cancer. New England Journal of Medicine 323:1228-1233, 1990
3. Eaden JA, Abrams KR, Mayberry JF: The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 48:526-535, 2001
4. Motzer SA, Jarrett M, Heitkemper MM, et al: Natural Killer Cell Function and Psychological Distress in Women with and without Irritable Bowel Syndrome. Biological Research For Nursing 4:31-42, 2002
5. Matsunaga H, Hokari R, Ueda T, et al: Physiological stress exacerbates murine colitis by enhancing proinflammatory cytokine expression that is dependent on IL-18. American Journal of Physiology – Gastrointestinal and Liver Physiology 301:G555-G564, 2011
6. Brody JS, Spira A: State of the Art. Chronic Obstructive Pulmonary Disease, Inflammation, and Lung Cancer. Proceedings of the American Thoracic Society 3:535-537, 2006
7. Rayet B, Gelinas C: Aberrant rel/nfkb genes and activity in human cancer. Oncogene 18:6938-47, 1999
8. Sovak MA, Bellas RE, Kim DW, et al: Aberrant nuclear factor-kappaB/Rel expression and the pathogenesis of breast cancer. The Journal of clinical investigation 100:2952-60, 1997
9. Solinas G, Marchesi F, Garlanda C, et al: Inflammation-mediated promotion of invasion and metastasis. Cancer metastasis reviews 29:243-8, 2010
10. Kim S, Takahashi H, Lin WW, et al: Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 457:102-6, 2009
11. Balkwill F, Mantovani A: Inflammation and cancer: back to Virchow? Lancet 357:539-45, 2001
12. Barber MD, Fearon KC, Ross JA: Relationship of serum levels of interleukin-6, soluble interleukin-6 receptor and tumour necrosis factor receptors to the acute-phase protein response in advanced pancreatic cancer. Clinical science 96:83-7, 1999
13. Wang CS, Sun CF: C-reactive protein and malignancy: clinico-pathological association and therapeutic implication. Chang Gung medical journal 32:471-82, 2009
14. Antoni MH, Lutgendorf SK, Cole SW, et al: The influence of bio-behavioural factors on tumour biology: pathways and mechanisms. Nat Rev Cancer 6:240-248, 2006
15. JACOBS JR, BOVASSO GB: Early and chronic stress and their relation to breast cancer. Psychological Medicine 30:669-678, 2000
16. Saul AN, Oberyszyn TM, Daugherty C, et al: Chronic stress and susceptibility to skin cancer. Journal of the National Cancer Institute 97:1760-7, 2005
17. Thaker PH, Han LY, Kamat AA, et al: Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nature medicine 12:939-44, 2006
18. Kiecolt-Glaser JK, Glaser R, Gravenstein S, et al: Chronic stress alters the immune response to influenza virus vaccine in older adults. Proceedings of the National Academy of Sciences 93:3043-3047, 1996
19. Davidson RJ, Kabat-Zinn J, Schumacher J, et al: Alterations in Brain and Immune Function Produced by Mindfulness Meditation. Psychosomatic medicine 65:564-570, 2003
20. Bianchini F, Kaaks R, Vainio H: Overweight, obesity, and cancer risk. The lancet oncology 3:565-74, 2002
21. Suh S, Kim KW: Diabetes and cancer: is diabetes causally related to cancer? Diabetes Metab J 35:193-8, 2011
22. Mathews EH, Liebenberg L: A Practical Quantification of Blood Glucose Production due to High-level Chronic Stress. Stress and Health:n/a-n/a, 2011
23. de Kloet ER, DeRijk RH, Meijer OC: Therapy Insight: is there an imbalanced response of mineralocorticoid and glucocorticoid receptors in depression? Nat Clin Pract End Met 3:168-179, 2007
24. Jee SH, Ohrr H, Sull JW, et al: Fasting serum glucose level and cancer risk in Korean men and women. JAMA : the journal of the American Medical Association 293:194-202, 2005
25. Dhabhar FS, Saul AN, Daugherty C, et al: Short-term stress enhances cellular immunity and increases early resistance to squamous cell carcinoma. Brain, behavior, and immunity 24:127-37, 2010
26. Ben-Eliyahu S, Yirmiya R, Liebeskind JC, et al: Stress increases metastatic spread of a mammary tumor in rats: evidence for mediation by the immune system. Brain, behavior, and immunity 5:193-205, 1991
27. Inbar S, Neeman E, Avraham R, et al: Do stress responses promote leukemia progression? An animal study suggesting a role for epinephrine and prostaglandin-E2 through reduced NK activity. PloS one 6:e19246, 2011
28. Ben-Eliyahu S, Page GG, Yirmiya R, et al: Evidence that stress and surgical interventions promote tumor development by suppressing natural killer cell activity. International journal of cancer. Journal international du cancer 80:880-8, 1999
29. Lawrence T: Inflammation and cancer: a failure of resolution? Trends in pharmacological sciences 28:162-5, 2007
30. Evans JF: Rofecoxib (Vioxx), a Specific Cyclooxygenase-2 Inhibitor, Is Chemopreventive in a Mouse Model of Colon Cancer. American journal of clinical oncology 26:S62-S65, 2003
31. Vanchieri C: Vioxx Withdrawal Alarms Cancer Prevention Researchers. Journal of the National Cancer Institute 96:1734-1735, 2004
 
© Caveman Doctor 2012. All Rights Reserved
 

Comments
8 Responses to “Can Excess Stress Cause Cancer?”
  1. CN says:

    Great article Dr. C! I’m sure you are helping many people fight cancer and stress.

    I like how you summarize key points at the end. You should write a book!

    Thank you!

  2. dow jones industrial average says:

    i love your blog, i have it in my rss reader and always like new things coming up from it.

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