Interrupting a cancer highway: How exercise may keep cancer from spreading
When cancer cells travel to another part of the body and form a new tumor — called metastasis — it can be deadly. Metastasis accounts for an estimated 90 percent of cancer deaths. One potential therapy to lower risk of premature cancer death, recurrence and metastasis is physical activity, says epidemiologist Justin Brown, PhD, of the Pennington Biomedical Research Center and an AICR grantee.
Brown, a current AICR grantee, recently co-published a paper proposing key mechanisms by which physical activity can affect cancer cells. Understanding how physical activity reduces cancer recurrence and mortality risks is one of the most provocative unanswered questions in oncology, he notes.
Here, Brown shares how exercise can help cancer patients live longer, and how research scooped from the engineering field could help reduce risk of metastasis.
Q: What are you studying with your AICR grant?
A: We are finding out that exercise is as powerful as drugs – our hope is we can prescribe exercise in a similar manner. This [research] can also inform other therapies to exploit these mechanisms. We recognize that not every patient can or is interested in exercising; this will help to inform other areas of research to enable cancer patients to live longer.
Q: Can you talk about the overall evidence related to physical activity and survival.
A: All of the evidence supporting a link between participation in physical activity after a cancer diagnosis with various outcomes — such as survival and recurrence — these are all observational studies. They show an association, but not a cause and effect. The evidence here is overwhelming that higher volumes of physical activity are associated with lower risk of recurrence, death from cancer and death from any cause. There is about a 40% reduction. The effect is independent of a lot of different factors, such as whether a person was a smoker, the tumor stage, older versus younger adults: physical activity is associated with a more positive long-term prognosis.
Q: Can you talk about the overall evidence related to recurrence and metastasis?
A: Where the cancer grows is often not what kills people. What kills patients is where the cancer spreads to – that’s the process of metastasis. For most cancer patients, certainly with colon cancer and many other solid tumors, the two major causes of death are either recurrence of cancer or heart disease. We know that exercise is good for heart disease as well. It can also reduce other competing cause of death. That’s also true with the general population.
Q: Research on physical activity and survivorship all seems so new. Is it accepted now?
A: There were two seminal studies: One in 2005 in JAMA on breast cancer and then another paper in 2006 related to colon cancer. Those were first two studies that demonstrate a link between physical activity after a cancer diagnosis with disease recurrence and death from cancer and overall survival. The data is in its infancy, the discoveries are only about 15 years old but now, over a dozen studies between post-diagnosis and physical activity have shown similar associations.
Q: What is known about the amount of physical activity needed?
A: Patients who derived the largest magnitude of benefit were sedentary before their [cancer] diagnosis and become most active after. But anybody who does some physical activity receives some benefit. We believe physical activity can be empowering and give [survivors] a sense of control; it allows patients to have some management and control of their disease.
Q: Your paper talks about key biological mechanisms to explain the associations seen with physical activity and metastasis, recurrence and survival. One familiar mechanism relates to the tumor microenvironment. Can you explain what this is?
A: The microenvironment has the growth factors and nutrients the cancer cells use to reproduce. Basically, it’s the air that the cancer cells breath in order to stay alive. One thing to remember is the area surrounding the tumor is dynamic – as tumor cells grow and proliferate they try and figure out ways to exploit the environment so they can get more nutrients.
Q: And how would physical activity affect this?
A: The hypothesis is that exercise effectively starves the cancer cells of the growth factors that they need. One example that we use is insulin. All of us have insulin in our bloodstream; we use it to get sugar into our cells. Cancer cells use insulin to grow. Exercise causes our body to use insulin more efficiently: insulin in our blood goes down, it deprives the cancer cells in the insulin it uses to grow and replicate.
Q: You also propose another mechanism that is not as familiar, relating to shear stress. How does this work?
A: We see from the breast or colon that a single or cluster of cancer cells breaks away from the primary tumor and gets in the bloodstream. It survives there and goes to other organs, such as the liver. When we think about how exercise can prevent metastasis, one of the features of exercise is that it increases shear stress.
When you exercise, your heart rate pumps faster to move more blood out and blood vessels get a little bigger to accommodate the increased blood flow. Pushing more blood through blood vessels means there are greater stresses put on the walls of the blood vessel. If you are a tumor cell that has broken away and find yourself in the bloodstream, there are immune cells trying to kill you and then the blood flow creates sheer stress; the stress is so physically stressful to the cancer cell that it cannot survive because on the surface of the cancer cells are mechanoreceptors, which gives them clues to its environment, that tells the cell that it’s not a great environment. We hypotheses that these mechanical receptors sense the stress and tell the cell to begin cell death – called apoptosis.
Cancer cells are not designed to live in the bloodstream, that’s their highway to other organs. If we interrupt that highway, we can stop that tumor cell from getting to that distant organ.
Q: How did you and your colleagues come up with this hypothesis?
A: In 2018, we reported the different ways that exercise can reduce circulating tumor cells and found that exercise reduces circulating tumor cells in patients with early colon cancer. Up until that point, most of the field thought it related to the nutrient availability, inflammation, growth factors, etc. We started to think: are there other means exercise could cause cancer cells to be reduced? We found interesting literature from the biomedical engineering field. They exposed cancer cells to various levels of sheer stress and established that exercise increases sheer stress and higher stress is related to fewer circulating surviving cells.
We are not the first to think of this – we were the first to connect this converging line of evidence to unify and explain the benefits of physical activity. The 2018 paper provided the platform for us to continue down this research that is, in part, supported with the AICR grant.