Some thoughts on stress, cancer and beta-blockers

The topic of stress and cancer is complex, emotional and controversial.

Many people diagnosed with cancer, understandably, want to know whether something that has happened in their lives could have led to their disease. And because many people have stressful lifestyles, they often ask whether stress could have caused their cancer.

The short answer is that it almost certainly didn’t.

The causes of cancer are a complex mixture of lifestyle, environment and genetics, as we wrote last year. And on top of this, population studies repeatedly fail to show a definite, concrete link between ‘being stressed’ and a person’s chance of developing cancer, as we’ll see below.

But the more researchers study the biological processes involved in stress, the more they’ve realised that cancer might subvert some of these for its own ends. And understanding how could yield clues as to how to treat the disease.

So although there’s an emerging link between cancer growth and the molecules involved in stress, this is a long way from saying ‘stress causes cancer’, or makes it worse.

This subtle but important difference was underlined by new research today in the journal PLoS Biology, looking at how stress-linked molecules might be involved in the spread of cancer. Disappointingly, the research was accompanied by a press release that overplayed the evidence on stress and cancer. And this led to some unfortunate headlines.

This is a shame, because the research itself is rather intriguing. It lends even more weight to the idea that simple drugs like beta-blockers might be a useful addition to doctors’ anti-cancer armoury – something our own researchers are studying.

But it would be a shame if this finding were clouded by emphasising the idea that stress causes cancer. People diagnosed with the disease have enough on their plate without being worried about being worried.

Let’s look at how the new research fits into the wider picture.

What is ‘stress’?

Psychological stress is something we all experience at some point in our lives, but about which our biological understanding is still evolving. According to the US National Cancer Institute:

Psychological stress refers to the emotional and physiological reactions experienced when an individual confronts a situation in which the demands go beyond their coping resources. Examples of stressful situations are marital problems, death of a loved one, abuse, health problems, and financial crises.

The body responds to stress by releasing stress hormones, such as epinephrine (also called adrenaline) and cortisol (also called hydrocortisone). The body produces these stress hormones to help a person react to a situation with more speed and strength. Stress hormones increase blood pressure, heart rate, and blood sugar levels. Small amounts of stress are believed to be beneficial, but chronic (persisting or progressing over a long period of time) high levels of stress are thought to be harmful.

But do they cause cancer, or even make it worse?

Evidence from population studies

Causing cancer

Many studies have looked at whether stress increases cancer risk, and their results are, to put it mildly, inconsistent. Here’s a sample of prospective cohort studies – i.e. they followed people over time and measured stress levels (usually via questionnaire) and whether people went on to develop cancer.

This Danish study, from 2001, found lower rates of bowel cancer among women who were stressed, but not among men, a finding weakly repeated in this Japanese study from 2005.

In 2003, a large Finnish study found a weak link to the number of ‘stressful life events’ in a woman’s life, but a 2005 study in the BMJ found a lower risk of breast cancer among stressed women.

A 2006 Danish study looked at overall cancer risk, and found no link to stress, while in 2007, stressed women were found to have lower rates of womb cancer.

A Japanese study in 2007 found that having ‘ikaga’, (a Japanese term meaning something that makes one’s life worth living) lowered breast cancer risk.

In 2009, a large US study found no link between stressful life events and breast cancer risk, nor did a 2007 prostate cancer study.

That same year, a UK study found a weak link between stress and breast and prostate cancer, but the authors felt that other factors may have confounded these results . And here’s a paper from 2010 that found higher rates of lung cancer among people who had a traumatic event in their childhood.

If there was a strong, clear relationship between lifetime stress and cancer rates, we wouldn’t see such inconsistent results from the research.

Making cancer worse

Other researchers have looked at whether psychological issues such as stress or depression might be mean people have a worse outlook for the disease (rather than an increased risk of developing it in the first place). Here the evidence from population studies is slightly stronger (but only slightly) – and there are important caveats.

Firstly, it’s hard to find cancer patients who don’t experience some form of anxiety or stress during their experience of cancer. This makes unpicking the relationship between stress and outcome difficult. On top of this, people who are stressed or depressed are less likely to complete their treatment, to seek help when they need it, and to smoke, drink heavily or be overweight.

So although some population studies have shown a statistical link between cancer survival and psychological stress (and we need to point out that others haven’t), it’s far from clear whether what we might call ‘the biology of being stressed’ is the culprit, or whether stress is a ‘marker’ for something else.

As a 2008 Cancer Research UK-funded meta-analysis in Nature Clinical Practice Oncology concluded:

[Our] analyses suggest that stress-related psychosocial factors have an adverse effect on cancer incidence and survival, although there is evidence of publication bias and results should be interpreted with caution.

In other words, even though the researchers saw an overall significant link, they weren’t convinced the effect was ‘real’, as opposed to being caused by problems with the studies’ design, or chance.

So what about laboratory studies? Can understanding the biology of stress shed any light on things?

Molecular findings

Laboratory scientists have been unpicking the molecular pathways involved in stress for decades, and testing if they’re related to, or involved in, cancer.

The findings of many of these studies are summarised in this 2006 Nature Reviews Cancer article, which describes a whole range of stress molecules and pathways that might be linked to cancer.

To pick just one example, research in 2010 (discussed here in Scientific American) showed that adrenaline (produced during stress) could encourage the growth of ovarian cancer cells in the lab, and in mice, by activating a molecule called FAK.

Again, another caveat needs to be brought in here: most of these studies have been carried out in mice, or in lab-grown cells. On their own they provide a compelling narrative, but when seen alongside the population results we discussed above, it’s far from clear whether any of these proposed mechanisms are actively involved in driving human cancers.

(And it’s worth remembering that there’s also evidence that the relationship might work the other way round)

Beta-blockers and cancer

And so to today’s research, from a group based at Vanderbilt University in Tennessee.

Published in PLoS Biology, the team showed that ‘stress’ signals from the central nervous system affected the bone marrow of mice – specifically, they increased levels of a protein called RANKL. This, in turn, made the mice’s bone marrow a much more inviting environment for the spread of breast cancer cells.

The team then showed that blocking the action of RANKL with drugs, or blocking the central nervous system signals with beta-blockers, slowed the spread of cancer to the bones in mice with breast cancer.

This is a nice new piece in an emerging jigsaw. Researchers have previously spotted that breast cancer survival rates seem to be higher among patients who are also taking beta-blockers for stress. One of these researchers is Dr Des Powe, whom we’re now funding to carry out a larger study to confirm this.

If the results hold up then, as he told us last September, the plan is to carry out a clinical trial of beta-blockers in women with breast cancer.

Worrying headlines

Finding more evidence that beta-blockers could help treat cancer is exciting. But it’s a far cry from saying “Stress might aid the spread of breast cancer to bone”, which was the title of the press release that accompanied the research.

As we’ve said before, the coverage of cancer research in the media can sometimes lead to patients feeling like they’re being blamed for their disease. This is unhelpful – as is the implication that worrying about your cancer might make it worse. But feeling stressed or anxious – or even depressed – is a perfectly natural reaction to being diagnosed with cancer.

Our concern is that focusing on stress, as well as being stressful in itself, can distract people from other things they can do to help themselves – either while healthy, or when undergoing cancer treatment (see, for example, our Coping with Cancer section).

As we’ve seen, the evidence around stress and cancer is far from concrete, and this is very much an emerging field. Despite this, many cancer patients believe that stress was linked to their diagnosis. This is understandable, but the evidence just doesn’t confirm it.

And unfortunate headlines and PR do nothing to help dispel one of most difficult-to-shift cancer myths of them all.

Henry

Reference

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• J. Preston Campbell et al (2012). Stimulation of Host Bone Marrow Stromal Cells by Sympathetic Nerves Promotes Breast Cancer Bone Metastasis in Mice PLoS Biology DOI: 10.1371/journal.pbio.1001363