Dr. Rhonda Patrick: So I want to talk a little bit about some of the mechanisms for improved survival, for reduced cancer recurrence. I mean, you mentioned one, which was continuing the treatment, right? So obviously that's one important—

Dr. Kerry Courneya: Absolutely.

Dr. Rhonda Patrick: But perhaps some other ones that may also affect cancer metastasis, right? Like that would also affect survival and perhaps recurrence later down the line as well. What do you find— can we talk a little bit about some of these mechanisms like immune-related, metabolic-related? I've heard you talk about increased blood flow.

Dr. Kerry Courneya: Yeah.

Dr. Rhonda Patrick: And maybe what's most compelling, if there's any that's most compelling.

Dr. Kerry Courneya: So if we talk about influencing the primary tumor, and we've seen this in preclinical models, but also in the human studies, sometimes when we've got an existing primary tumor, the first treatment is not to surgically remove it. The first treatment is to treat it with chemotherapy or radiation therapy, and try and shrink or eliminate the tumor that way. And so what they've shown in some of these preclinical models is, if you're giving these mice a particular chemotherapy drug and exercise versus neither versus both, exercise combined with chemotherapy is more effective than exercise alone or chemotherapy alone. And what they've shown in these studies is, that these primary tumors have a very poor vasculature. It's poor quality blood vessels, they're leaky, and they're chaotic in there.

But all these tumors, in order to grow, they need to draw blood vessels. They only grow to a very small size, and unless they get blood vessels within them, they can't grow any larger. So they all start developing these blood vessels. What they were able to show in these exercise studies, that exercise improves the quality of these blood vessels, and the density of these blood vessels. And while you're improving the quality of these blood vessels, what that improved was chemotherapy delivery to the tumor. So it improved the delivery of the drugs to the tumor. What it also does is improve perfusion to the tumor, and these tumors become better oxygenated. That's critical. Because radiation therapy is effective with well-oxygenated tumors.

If they are hypoxic tumors, they're not radiosensitive. So now we start thinking, if you're exercising while getting radiation therapy, or while getting chemotherapy, we might improve delivery of the drugs to the tumor, and improvements in making them more radiosensitive. And we've seen this in actual human studies. So in actual studies with patients, we did a study in rectal cancer patients, and the treatment for them is a combination of chemoradiation therapy prior to having the tumor surgically removed 12 weeks later. So they want to shrink and try and eliminate that tumor. And what we found is the patients who exercise while getting this chemoradiation therapy were more likely to have a complete response, meaning the tumors were completely gone prior to having the surgery.

So this is a very profound and important benefit of exercise, potentially, in these patients who are getting treated with what we call neoadjuvant therapy, this kind of chemo and radiation therapy prior to surgery. So that's one very important mechanism, and perhaps the most compelling. Once the tumor is surgically removed, you're no longer concerned about the primary tumor, you're concerned that a small number of cancer cells have been shed from the primary tumor and might spread throughout the body. So these cells have to go on an arduous journey through the vasculature. So they can spread through the lymph system, but also through blood vessels.

And there's some really interesting research suggesting that if you exercise while the tumors are shedding these circulating tumor cells, those circulating tumor cells are less likely to survive because of the increased shear stress. So when blood's flowing through the vasculature, it's under a certain amount of pressure, but of course, that's dramatically increased when you exercise. And these circulating tumor cells are far more likely to die and not survive that journey if you're exercising. So this is another really interesting mechanism for how exercise might be able to prevent the spread of a primary tumor. And once those cells are circulating, or they've kind of disseminated elsewhere in the body. This is where some of these other mechanisms can be important.

Exercise can reduce insulin and IGF, signals that help cancer cells grow and divide more rapidly. The anti-inflammatory effects of exercise can be very important. And probably one of the key ones is immune system tracking down and killing these cancer cells, right? This is why we have the whole new treatment now, immunotherapy. We've realized how important it is to call on the immune system to be able to track down and kill these cancer cells. So exercise, in some ways, was the original immunotherapy. You know, this was stimulating the immune system and improving natural killer cell cytotoxicity, the number of natural killer cells, the number of T cells and B cells that were all doing immunosurveillance of these cancer cells.

So lots of good biological mechanisms for how exercise might improve these cancer outcomes.

Dr. Rhonda Patrick: That was phenomenal. Thank you for that explanation. A couple of follow-up questions. So one, what you were just talking about, you know, the immune surveillance, and I'm wondering, so I've read some studies about exercise and these are normal healthy people. And, you know, for a long time it was thought like, oh, if you're sick, if you have a respiratory illness, you should not exercise because some studies that were done found that exercise acutely lowered the number of circulating T cells in the bloodstream, in the vascular system. But then subsequent studies were done and found that actually those circulating T cells were going somewhere. They're actually going to the lungs.

So they're mobilizing, going to the lungs to help fight off, you know, pathogens, right, the respiratory— causing the respiratory illness. Does exercise affect the immune cells like the cytotoxic T lymphocytes or the natural killer cells mobilizing to go to the site of the tumor, as well as, you know, surveilling in the vascular system?

Dr. Kerry Courneya: Yeah. So that's been demonstrated in those preclinical mouse models. So they've shown that the mice that exercise will have higher numbers of T cells, natural killer cells within the tumor itself. So, that improved blood flow allows everything to get into the tumor in order to be able to kill it.

So, yeah, the improved immunity, it will push all the immune cells out into the system to potentially track down some of these circulating or disseminating tumor cells, but it also increases immunodelivery to the actual primary tumor as well. Now, exercise, to your point, can be immunosuppressive as well, right? We know these very high levels of exercise that kind of triathletes and the marathon runners, right? It can cause immunosuppression. And this was one of the reasons some oncologists early on were concerned about exercise, right? These patients can become immunosuppressive from the chemotherapy treatments and other treatments. So they were a bit concerned with the very high-intensity exercise in these patients.

But most of what we're studying and looking at is more the moderate intensity, or the higher intensity exercise, but for reasonable amounts of exercise, not sort of these marathon runners or these triathletes, athletes where you might overwhelm the patient.

Dr. Rhonda Patrick: And most people aren't out there running marathons, so it seems kind of silly to be so concerned about immunosuppression when a very small percentage of people are overtraining in that regard, right?

Dr. Kerry Courneya: Yes. Yeah, we don't have a public health concern about too many people exercising too much. It does happen. There is such a thing as exercise addiction and overdoing it and overtraining, but that is a very small slice of the population.

Dr. Rhonda Patrick: My second question is, you were talking about the shearing forces of, you know, increasing blood flow and that can kill these circulating tumor cells. There's a variety of ways you can increase blood flow through various forms of exercise. So, for example, aerobic exercise, it's on a continuum, right? The higher the intensity you go, the stronger the sort of push of blood flow, you know, cleaning out the system. Resistance training. So lifting weights can also cause blood pressure changes and changes in blood flow. Do you think both of those types of exercise could affect that pathway, or is it mostly the more higher-intensity sort of aerobic exercise?

Dr. Kerry Courneya: Yeah, based on the mechanism, then anything that increases that blood flow should work.

So some of the research that's been done has been more of a preclinical in vitro model. So there's researchers who developed these plastic tubes, rubber-like tubes, and they can spin blood through these tubes faster or slower. And then they can put these circulating tumor cells in these— this sort of microfluidic system that they've developed, and they can spin them around faster and slower. And they show that the faster you spin these around, consistent with what might happen during exercise, the more of these cells that die. So they've not looked at what's causing that increase in blood hemodynamic shear stress. So yeah, in theory, both strength training and aerobic exercise should be able to do it.

The one study that's been done in humans showing that exercise improves or reduces circulating tumor cells was an aerobic exercise program. But in theory, both should work.

Dr. Rhonda Patrick: And if you do reduce the number of circulating tumor cells in your vascular system, is that associated with— is there data showing that is associated with lower, you know, cancer recurrence, lower cancer mortality, for example?

Dr. Kerry Courneya: That's right. So the way that cancer spreads is the— these— it has to shed cells from the primary tumor, and they have to circulate throughout the blood vessels, and they have to get somewhere else. And so if you're preventing that or reducing that, you should be able to reduce the number of metastases. That's absolutely critical. Because that's what ultimately kills cancer patients, right?

So breast cancer, prostate cancer, you think of these cancers, the breast is not a vital organ. Women can live without a breast. So how do you die from breast cancer? Prostate cancer, men can live without a prostate. How do you die from prostate cancer? It's because these tumors shed these cells and they disseminate throughout the system, and then they arrive at places like the brain, the lungs, the liver, and the bone, and they set up what we call sort of colony tumors there, and they begin to grow and invade those organs. And that's how you ultimately die from breast cancer. If it's localized, you're not going to die from breast cancer. And so preventing that spread is really the critical aspect, and so reducing the number of circulating tumor cells is critical.