Stress, inflammation, and cancer

This blog gives an overview of recent findings from the field of psychoneuroimmunology: the intersection of psychology, biology, and immune function.

This blog is partly the story of how stress acts on a molecular level to increase our chances of getting cancer and of cancer progression. The more important part is the story of how de-stressing might help our immune systems function better and help to improve our health. Research from the field of psychoneuroimmunology – psychology, neurology, and disease – helps us to understand, in a practical way, how stress affects our bodies. In deepening our understanding of what is happening in our bodies, perhaps we can thoughtfully harness our mind-body-spirit approach and use it to our advantage. Read on to learn more about the connection between stress, inflammation, and cancer.

Inflammation: A molecular story

We have heard a lot about inflammation and disease. But what exactly is inflammation, and why is it harmful? Inflammation happens in our bodies, and it’s not all bad. In fact, inflammation is vital for healing; it’s how our bodies fight disease and repair damage. The problem is with chronic inflammation. This increases the risk of a variety of diseases.

A group of chemical messengers called cytokines play an important role in inflammation. Cytokines are secreted by cells to regulate the body’s immune response. When a cell secretes a cytokine, that cytokine binds to other cells. The receiving cells carry out activities based on the cytokine’s message. These activities can include cell inflammation, growth (proliferation), and death (apoptosis).

Cytokines and inflammation

Our bodies' chemical messengers

Some cytokines cause inflammatory responses. These cytokines are usually secreted by immune system cells. It works like this: when a cell is injured by bacteria, trauma, toxins, etc., it releases chemicals which cause fluid to enter the cells; this signals the immune system to repair damaged tissue and fight infections.

When our bodies are functioning well, cytokines are rapidly released at the area of infection, which causes inflammation. The inflammation calls other immune system cells to come to the area for repair or to fight infection. When the crisis is over, anti-inflammatory cytokines come to the site to counteract pro-inflammatory activity and calm the immune response. Our bodies need to have a healthy balance between inflammatory and anti-inflammatory cytokines. An imbalance leads to chronic inflammation and diseases like cancer.

Cytokines: types and activities

There are several subsets of cytokines. One of these are interleukins, which play an important role in inflammation. They also regulate cell growth. Researchers have been investigating the role of interleukins in cancer. The pro-inflammatory interleukins IL-1 and IL-6 seem to play roles in breast cancer tumor growth, as does the anti-inflammatory IL-4. Another cytokine that is important in cancer tumor growth and apoptosis is Tumor Necrotic Factor alpha (TNF α). Type II Interferon or IFNγ is a cytokine that activates macrophages, the large white blood cells that gobble up infections and unhealthy cells; IFNγ is also implicated in cancer.

Cytokines are produced by certain T lymphocytes (a kind of white blood cell). Th1 lymphocytes produce the cytokines IL-1β, IL-2, IL-12, TNF-α, and IFN-γ, which are associated with fighting infections. Th2 lymphocytes produce the cytokines IL-4, IL-5, and IL-10, which are associated with tumor growth and metastases. Chronic stress and inflammation seem to lead to a dampening of the production of Th1 lymphocytes and the anti-inflammatory cytokines they produce, and an overproduction of Th2 lymphocytes and the inflammatory cytokines they produce. However, it’s not a simple, too-many-inflammatory/not-enough-anti-inflammatory cytokine equation. The system is complex, and each cytokine can, paradoxically, help or harm tumor growth.

It’s not all about the genes: The role of RNA

It's about the copying

The “maybe good news, maybe bad news” effect of these cytokines is probably the result of the complex micro-environment in which they exist. However, one common denominator seems to be the action of these cytokines on the transcription of ribonucleic acid, or RNA. RNA is the stuff inside all cells that allows for protein synthesis. Protein synthesis is essential for life; making protein is important because proteins give our bodies their structure and allow us to metabolize food, repair and rebuild tissue, maintain fluid balance, and regulate pH.

RNA helps produce, or synthesize, the proteins; DNA holds all the instructions for producing them. The instructions are part of our genetic code, contained in the double-helix string of paired molecules, or nucleotides, inside the nuclei of our cells.

RNA at work

RNA carries out the instructions, creating proteins in a process called transcription. First, DNA’s double helix is split at the transcription site. Next, proteins (transcription factors) and enzymes (RNA polymerase) bind to and copy the material in the DNA strand, thus creating a single strand copy of the gene. This strand travels outside the nucleus and into the cytoplasm, over to the ribosomes (the factory of the cells) where it binds with more RNA and certain amino acids to create proteins – including cytokines.

While we often focus on DNA and our genes as the source of illness, that is not the entire story. The problem could occur at the RNA transcription level. Even when DNA is correctly sequenced, RNA might make changes that allow for tumor growth and proliferation. There is a specific transcription factor, nuclear factor kappa-beta, which regulates several cytokines including interleukins and TNF. It seems that errors in this transcription process are at play in the process by which chronic inflammation can cause disease.

The HPA axis: Stress and immune function

The hypothalamus-pituitary-adrenal axis helps our bodies respond to stress. Neurons from the hypothalamus (a part of your brain’s emotional or limbic system) send signals to the pituitary body, which we often call the master gland. Then, the pituitary secretes a hormone called ACTH that signals the adrenals to release the stress hormone cortisol. Cortisol causes a release of glucose in the blood and raises our heart rate and blood pressure.

We have all felt the effects of cortisol. When we are frightened, it, along with adrenaline, gives us that rush. When we are stressed or anxious about something, it gives us that uneasy feeling. Remember being a kid listening to a scary story: even if it was for fun, your brain’s hypothalamus sent signals to your pituitary body, asking it to release ACTH. That hormone went to your adrenal glands, all the way down by your kidneys, and asked them to release cortisol. The cortisol flowed into your blood stream, increasing your blood pressure and heart rate; it also made your blood sugar levels increase so you would have energy to run away. You were ready to run, even though the scary story was just for fun. A well-functioning HPA axis is even more useful when the stress you face is real.

The role of chronic stress

However (and thankfully) most of the time our stress is not really an imminent threat. Our modern stressors are less likely caused by the bear in the woods than by thinking about and relating to ongoing stressful things like horrible bosses, dysfunctional relationships, health concerns, or dwindling bank accounts. These stresses tend to be chronic, and they are not good for us.

When we experience chronic stress, our HPA axis can be come dysregulated. Instead of a short-term burst of cortisol, we have chronically elevated levels; in time, the levels become depleted, so we don’t have store available during a crisis. Generally, chronic stress seems to lead to an elevated level of cortisol, with its resultant increase in blood sugar and cardiovascular activation. In some cases, chronic stress, especially the kind experienced during childhood, seems to lead to less ACTH, and less cortisol, being available when needed. In both cases, an inefficient stress response leads to chronic inflammation and an increased risk of disease. This is the role of inflammation in the stress, inflammation, and cancer cycle.

Circling back to the cytokines: Chronic psychological stress and the cortisol it releases seem to cause our bodies to produce more Th2 cells than Th1 cells. This imbalance might cause our bodies to produce more of the cytokines that are associated with tumor growth and metastasis. Again, there is not a simple causal relationship between these cytokines and every kind of cancer risk, but in some cases, a correlation seems to be at play.

About those genes: BRCA, cortisol, and cancer

We have all heard of the BRCA mutations, which are linked to an increased risk of developing breast and gynecologic cancers. BRCA genes are important in DNA repair and apoptosis. Some studies, like this one, have shown that, when cortisol levels are high, cells do not efficient repair damage and they experience increased oxidative stress. The same study found that women who had elevated cortisol levels were more likely to develop cancer. Other studies have shown that BRCA1 is downregulated when exposed to high cortisol levels, making it less efficient at repair and apoptosis. Stress seems to directly impact the function of BRCA. Indeed, stress could be the link that connects this gene to the development of breast cancer.

Hope

In this blog, we explored a world of microscopic interactions which seem come together to form the link between stress, inflammation, and cancer. While researchers are learning more, we clearly have not figured out the whole picture. What seems to be at play is a combination of events: exposure to a carcinogen, a genetic predisposition, faulty RNA, an imbalanced immune system, stress and the HPA axis dysregulation with its consequent hormonal exposure – all of these paint part of a picture of what might have gone awry.

What can we do about it now? We have seen how stress seems to be directly related to disease progression; might de-stressing help stop or slow disease progress? The anti-stress benefits of biofield therapies, meditation, mindfulness, yoga, and some forms of talk therapy are well understood. Research is underway, demonstrating the effectiveness of various practices in slowing disease progress. Now is the time to hold up hope for ourselves and our community. Let's work to harness the mind-body-spirit connection to increase our wellness and improve our health outcomes.

by Sarah Murphy