Exercise and cancer: what's REALLY going on inside the body?

exercise Sep 27, 2018

In the previous post, I talked about how we human beings have evolved to move. Historically, the more athletic we were, the more likely we would be to survive (you know, outrun a bear, hunt our own food, etc. etc.).

And really this is largely why we find athletic bodies so attractive. Yes, this is driven somewhat by our powerful media obsession with perfect looks, but it goes back thousands of years to ancient Greece and the first Olympics (at least!). In fact, I heard someone tell me once that if you weren’t up to par and didn’t maintain a certain level of fitness, you’d be booted out of Greece and could no longer claim citizenship! I haven’t validated that with research myself, but I did think it was interesting…!

However, although we may not have necessarily been aware of the fact that athleticism = survival, as our bodies adapted and evolved to become more physical, our cells also adapted and that is what I want to focus on today.

Last week I read a review article [1] on the molecular effects of exercise on cancer and when I went out for a run later that day, I found myself thinking about what was going on inside my body at the molecular level and how it might be helping protect me. So, I want to summarize some key points here (but also acknowledge this is not exhaustive!).

We’ve known for some time that people who participate in physical activity and exercise during their leisure time have a reduced risk of developing at least 13 different cancer types [2]. And if you’ve already had cancer, particularly breast, colon and prostate cancer, exercise can reduce your risk of developing a secondary tumor [3].

But how does exercise help with cancer? Physically what happens inside the cells in our bodies to make these benefits happen?

Broadly speaking, there are three types of benefit: 1) the impact of exercise on the tumor itself; 2) exercise alleviates the side effects of the cancer itself and its treatment on the patient; and 3) exercise improves the effectiveness of the cancer treatment.

Let’s take a look at each one of these categories in turn:

The impact of exercise on the tumor itself

When you exercise, you have a range of different physiological responses to this additional strain you’re putting your body under, including an increase in blood flow, which in turn results in something called shear stress on the cells that line your blood vessels. Not only this, your pH balance is altered, your core body temperature increases and your sympathetic nervous system is activated as well (this is your involuntary nervous controls that govern things like your breathing, your heart rate, your ability to sweat, and so on). In addition to these larger scale changes, at the molecular level your muscles will secrete hundreds and thousands of tiny proteins called myokines [4]

Together, these changes have been shown to regulate tumor growth, its potential to spread, its metabolic activity and its ability to be detected by the immune system. Let’s take a look at some of the detail.

 

Effects on tumor growth and spread:

Exercise has been shown to reduce the rate of cancer cell growth in the lab by as much as 67%! But before we get too excited, unfortunately exercise on its own is not capable of getting rid of tumors in the body, in mice or in humans, and there isn’t any evidence yet to show that it can markedly reduce the size of already established tumors.

But where things do get a little bit exciting is with the effects of exercise on tumor metastasis. If you take cancer cells and culture them in the lab with serum taken from people who have been exercising, and then inject these cancer cells into mice*, this forms fewer tumors than if the cells were incubated with normal serum (*see footnote below on animal models). In other words, exercise does something to the body, and this “something” is released into the blood stream (which is where serum is extracted from). But what exactly does it do?

Well, this is where things get rather complicated, and it’s hard to distil 18 years of learning into one blog post….but here goes nothing!

There is a signaling pathway that is activated during organ formation in growing embryos called the Hippo signaling pathway. Normally, once the organs have finished forming, this pathway is switched off. But in cancer, it is aberrantly switched back on again. This helps the tumor to grow its own supply of blood vessels through the process of angiogenesis. However, repeated bouts of exercise actually switches this pathway back off again, which in turn means the tumor can’t grow its own blood vessels, and therefore it effectively gets starved of the nutrients it needs to grow.

…And this is just one way in which exercise can inhibit tumor growth!

Effects on tumor metabolism:

Every cell in the body uses glucose as its principal source of fuel – including both your healthy cells and any cancerous cells lurking about – and they do this through a metabolic process called glycolysis. But where they differ is in the way they break this fuel down for energy. Cancer cells metabolize (break down) glucose via a process called aerobic glycolysis, which is relatively energy-poor – in other words, cancer cells produce less energy per molecule of glucose consumed than healthy cells.

As a result, they are more susceptible to exercise-induced energy stress, as well as other stressors such as fasting and caloric restriction. Think about this for a minute. Exercise is a STRESSOR. It causes our bodies temporary stress. But this is a GOOD THING because it actually causes our old, damaged, long-in-the-tooth cells to die off first. And the more you expose yourself to stress in the form of exercise, and crucially include adequate recovery time too, the more you are training your body to recover from stress. You are, in effect, building a “molecular resilience”.

Anti-tumor immune response:

One of the most fascinating pieces in the review was about the effects of exercise on our immune cells, specifically on the immune cells involved in the anti-tumor immune response. We have numerous different immune cells in our body that make up our army against invading pathogens and rogue cancer cells. Amongst the types of immune cells involved in the anti-tumor immune response are natural killer (NK) cells and cytotoxic (or killer) T cells. Patients who have more NK cells and cytotoxic T cells in and around their tumors typically do better than patients with fewer anti-tumor immune cells [5]. Check out this video of T cells attacking cancer cells:

Image result for t cell attacking cancer cell

Image courtesy of Hybrid Medical Animation.

In humans and mice, exercise mobilizes NK cells and cytotoxic T cells, and emerging evidence in mice suggests that exercise can increase the levels of chemokines in the circulation, which serve to attract these immune cells to the tumor site [1]. So, in other words, participating in exercise helps boost your anti-tumor immunity.

But HOW exactly does this work? Well, as we exercise, this increases the rate of blood flow as it whooshes through our veins, and this causes shearing stress forces on the cells that line our blood vessels. This “injury” sends out SOS signals in the form of adrenergic hormones [6], which in turn stimulates the recruitment of these immune cells to the site of injury and also stimulates their growth and division. These mobilized immune cells then seek out and destroy transformed cancerous cells.

Heat:

Of course, when you exercise your core body temperature increases. This hyperthermia can delay tumor growth because it also increases the amount of NK cells brought into the area [7]. In fact, hyperthermia is currently being used in treating certain cancers [8], although the temperatures reached during such treatments is higher than what is typically reached with exercise [9].

Myokines:

As we exercise, our muscles are stretching and contracting repeatedly, and as they do so, they secrete hundreds of tiny proteins called myokines. These myokines are released into the circulation and are able to affect tissues and organs at a completely different site in the body. Best estimates are that there are around 600 different myokines in the ever-expanding list of myokines secreted during exercise! So, how do they affect cancer? Well, in the lab, some are able to trigger cancer cell death (e.g. Oncostatin M (OSM) and Irisin both inhibit breast cancer cell viability [10]), and others block tumor formation (e.g. SPARC reduces colon tumor formation in mice [11]).

More indirectly, myokines released by exercising skeletal muscle can also affect the activity of anti-tumor immune cells, for example, IL-15 can stimulate the growth, division and maturation of NK cells and T cells [12]. For this reason, IL-15 is currently being explored for use in boosting immune responses in cancer patients as an adjuvant treatment [13].

These effects are all seen immediately after a bout of exercise (we call this “an acute bout of exercise”), but if a person takes part in exercise training over a longer term, these acute effects build up together and eventually lead the tumor to adapt to the body’s new-found fitness. With more blood vessels perfusing the tumor, an improved anti-tumor immune response, and adjustments in cell metabolism (how it breaks down sugar for fuel), the end result is slower tumor progression.

So, you can tell your patients that even though they may see immediate benefits from exercise, the best results come from prolonged exercise training.

Exercise alleviates the side effects of the cancer itself and its treatment on patients

Some of the most prevalent and serious cancer-related symptoms include loss of muscle mass through sarcopenia and cachexia, as well as the impact on mental health, including anxiety and depression [14]. These factors are all linked to poorer outcomes, and can all be alleviated by exercise.

Prevention of muscular impairments and cancer cachexia:

For some patients, severe and rapid weight loss caused by muscle wasting is a real issue. For some cancers (e.g. gastro-intestinal, lung and pancreatic cancer), cachexia is caused by factors secreted by the tumor itself into the circulation. In other cancers, however, it is the chemotherapy that causes the muscle wasting. Typically, this is due to a combination of treatment-induced anorexia (feeling so sick you can’t stomach the thought of eating), physical inactivity (because you’re too exhausted or in too much pain to move) and also directly through muscular protein degradation. In mice at least, this muscle wasting can largely be prevented by exercise, and can also restore normal eating habits because exercise also stimulates the release of the appetite-regulating hormone, ghrelin. The corresponding study in humans has yet to be done, but it wouldn’t surprise me if the outcome was similar.

Depression and cognitive function:

Cancer treatment often causes depression, anxiety and cognitive problems amongst patients, and when depression kicks in, this can lead to patients not following their treatment regimen properly [15]. Exercise, particularly endurance training, can alleviate these symptoms [16]

How exercise can improve the effectiveness of cancer treatment

One of the many benefits of exercise for cancer patients is the effect it has on lowering the toxicity of treatment in healthy tissues [17], yet potentially even strengthening its toxicity against cancer cells. In other words, it makes the healthy cells tougher and more resilient to treatment, but without compromising the effectiveness of treatment against the cancerous cells. For example, for radiotherapy to be effective, there must be plenty oxygen delivered to the tumors in order to generate reactive oxygen species (ROS), which damage cell DNA and triggering cell suicide [18]. But of course, tumors are often hypoxic – that is to say, they lack oxygen – particularly in the center. Exercise naturally causes an increase in the circulation of blood and oxygen to peripheral tissues, and it also increases the amount of blood being perfused into a tumor mass. And so, over time, this results in new blood vessel growth in the tumor and ultimately increases the amount of oxygen being supplied to the tumor, which in turn increases the effectiveness of radiotherapy treatment.

Image result for radiotherapy

In the same way, the effectiveness of both chemotherapy and immunotherapy also rely on having enough blood perfusion in the tumor mass in order to deliver the toxic drugs and immune cells to the inner core of the tumor.

Of course, on the flip side, cutting off blood flow to a tumor mass can also be used as a treatment strategy to effectively starve the tumor. This is the basis on which anti-angiogenic therapies work – they prevent the growth of new blood vessels that tumors need for their own growth and survival. So, in this case, exercise and anti-angiogenic therapies are actually working in opposition to one another, and so care must be taken when advising patients on anti-angiogenic therapies about exercise regimes they can safely participate in.

Finally, surgery is still the most effective curative treatment for cancer, and getting exercise before an operation can actually improve the physical capacity of frail patients, which in turn lowers complications afterwards. It can also often reduce the length of time a patient stays in hospital following surgery [19].

The bottom line

Although exercise is not necessarily going to cure your patients of cancer, it is clear that moving more and sitting less has so many benefits for cancer patients that it’s certainly worth encouraging more exercise. Not only can exercise prevent secondary recurrence, but it can also alleviate the side effects of the cancer itself as well as its various treatment strategies. In addition, it can improve the effectiveness of the current three mainstays of cancer treatment: surgery, chemotherapy and radiotherapy.

And then of course there’s the fact that exercise can prevent the onset of cancer in the first place!

But what kind of exercise counts? And how much is enough? Or how much is too much? How often? What level of intensity? And so on and so on….

All great questions! And unfortunately, not easy ones to answer. The evidence, as it stands currently, indicates that moderate to high-intensity endurance exercise is better than light exercise when it comes to targeting the factors that act directly on tumor growth. Resistance training is good for preventing cancer cachexia and muscle degeneration. But it’s also important to remember that every patient is different, and just as drug therapies may work for some patients and not for others, equally exercise interventions may be more successful for some patients than for others.

Regardless, the next time you tell your patient to pull on their trainers to go out for a run, or hit the gym for a weights session, or even hit their local Zumba class or Clubbercise session, know that you are helping them to protect themselves from at least 13 different cancers, and that you may also be helping them by lowering their risk if secondary metastases.

If you're interested in learning more about the science behind cancer and how it thrives, check out this new mini-course here. It's the perfect introduction to the field, suitable for anyone who works with cancer patients and survivors, and wishes to start learning more about cancer.

One more thing!

I’d love to have you join the mailing list so I can keep you posted on any news and events that I think might interest you. All I need is your name and email address – and don’t worry, we're not email crazy at Essential Cancer Education so you won't find your inbox blowing up with hundreds of emails! Typically, you can expect to receive one email a week, with some additional surprises now and again when I have something special to share with you that I don't want you to miss. Sign up here.

 

*Injecting tumor cells into mice is a classic method of measuring the ability of tumour cells to seed a new tumor and spread – I personally do not do these kinds of experiments, partly because our university doesn’t work with animal models, but also because I don’t wish to do any animal testing! I just felt the need to state that, should any readers have any concerns. 

© Essential Cancer Education

 

References:

[1] Hojman et al., 2018

[2] Moore et al., 2016

[3] Holmes et al., 2005; Kenfield et al., 2011; Meyerhardt et al., 2006

[4] Hawley et al., 2014

[5] Ferrone and Dranoff, 2010; Pages et al., 2010

[6] Idorn and Hojman, 2016

[7] Chen et al., 2006; Fisher et al., 2011

[8] Gao et al., 2016

[9] Gonzalez-Alonso, 2012

[10] Gannon et al., 2015; Hojman et al., 2011

[11] Aoi et al., 2013

[12] Marcais et al., 2014; Satoh-Takayam et al., 2010

[13] Conlon et al., 2015

[14] Caruso et al., 2017; Christensen et al., 2014

[15] Lin et al., 2017

[16] Cooney et al., 2013

[17] Schmitz et al., 2010

[18] Chen and Kuo, 2017

[19] Cavalheri and Granger, 2017; Singh et al., 2013

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