the muscles. Notably, exercise induces acute
increases in epinephrine and norepineph-
rine, stress hormones released from the adre-
nal gland that are involved in recruiting NK
cells in humans. Murine studies show that
NK cells can signal directly to cancer cells. In
Dethlefsen’s study, when breast cancer cells
incubated with serum obtained after a bout
of exercise were then injected into mice, they
showed reduced tumor formation. The exer-
cise-induced suppression of breast cancer cell
viability and tumor formation were, how-
ever, completely blunted when we blockaded
β-adrenergic signaling, the pathway through
which epinephrine and norepinephrine
work.^12 These findings suggested that epi-
nephrine and norepinephrine are responsible
for the cancer-inhibiting effects we observed.
Epinephrine and norepinephrine, which acti-
vate NK cells, have also been shown to act
on cancer cells through the Hippo signaling
pathway, which is known for regulating cell
proliferation and apoptosis. Exercise-induced
spikes in these stress hormones activate this
pathway, which somehow inhibits the forma-
tion of new malignant tumors associated with
metastatic processes.Calling the immune system
In addition to acting directly on tumors, the
myokines released during and after exercise
are known to mobilize immune cells, par-ticularly NK cells, which appear to be
instrumental to the exercise-mediated
control of tumor growth in mice.
The late molecular biologist Pernille
Højman of the Centre for Physical Activ-
ity Research at Rigshospitalet was a leader
in discerning this mechanism. In the study
described above that compared tumor
growth in active and sedentary mice,
on which I was also an author, Højman
looked more closely at the tumors and
found that the running mice had twice as
many cytotoxic T cells and five times more
NK cells than those animals housed with-
out a wheel.
Højman repeated the experiment on
mice that had been engineered to lack
cytotoxic T cells. Again, she found that
mice with access to running wheels had
smaller tumors. When she performed
the same test on mice that had intact T
cells but lacked NK cells, the tumors of
all the mice grew to the same size. This
suggested that the NK cells, and not the T
cells, were the link between exercise and
tumor growth suppression.^8
Work by other groups had demon-
strated that epinephrine has the poten-
tial to mobilize NK cells, and Højman
and the rest of our team wondered if
epinephrine had a role in mediating
the anticancer effects of exercise. WeEXERCISE AND DEPRESSION
Depression is a severe adverse effect of cancer and cancer therapy. The risk of depression can be as high as 50 percent for some
cancer diagnoses, although this number varies a great deal depending on cancer type and stage (J Natl Cancer Inst Monogr, 32:57–71,
2004). In addition to its effects on a patient’s quality of life, depression can hinder compliance with treatment, and it’s a risk factor
for mortality in cancer patients (Lancet, 356:1326–27, 2000). In recent years, healthcare providers have increasingly integrated physi-
cal exercise into the care of cancer patients with the aim of controlling disease and lessening treatment-related side effects, while
researchers have amassed evidence supporting the assertion that such training can lower symptoms of depression in these patients
(Acta Oncol, 58:579–87, 2019). The biological mechanisms behind this beneficial effect remain to be determined, although some
clues have emerged.
For example, a study in mice found that exercise-dependent changes in metabolism result in reduced accumulation of some neuro-
toxic products (Cell, 159:33-45, 2014). In cancer patients, systemic levels of kynurenine, a neurotoxic metabolite associated with fatigue
and depression, are upregulated (Cancer, 121:2129-36, 2015). In mice, exercise enhances the expression of the enzyme kynurenine ami-
notransferase, which converts kynurenine into neuroprotective kynurenic acid, thereby reducing depression-like symptoms.
Findings such as these, together with exercise’s well-documented effects in alleviating depression among patients without cancer,
suggest that incorporating exercise into cancer treatment may benefit mental as well as physical health.
NK cells appear to
be instrumental to
the exercise-mediated
control of tumor
growth in mice.