| dc.description.abstract |
<p>Over the past decade, exercise has gained increasing attention from both clinicians
and patients as a beneficial adjunct therapy to maintain or enhance quality of life
in breast cancer patients. Recent epidemiological studies indicate that aerobic exercise
following a diagnosis of breast cancer may be associated with reductions in cancer-specific
and all-cause mortality. However, the mechanisms by which physical activity affects
tumor physiology are poorly understood. Accordingly, clinicians lack critical information
to properly advise breast cancer patients on the use of exercise as an adjunct to
more conventional therapies.</p><p>The beneficial effects of exercise on systemic
vasculature are well known, including improved endothelial function and increased
perfusion. In this work, we evaluate the hypothesis that exercise slows tumor growth
and improves the structure and function of tumor blood vessels, resulting in decreased
hypoxia and increased effectiveness of cyclophosphamide chemotherapy </p><p>To investigate
the effects of exercise on tumor microenvironment, we injected syngeneic 4T1 breast
tumor cells into the mammary fat pad of immunocompetent BALB/c mice. The exercise
intervention (voluntary wheel running) was designed to mimic four clinically relevant
scenarios: 1- patients who are sedentary before and after diagnosis, 2- previously
sedentary patients who begin exercising after diagnosis, 3- previously active patients
who stop exercising after diagnosis, and 4- previously active patients who continue
to exercise after diagnosis. Animals in Groups 3 and 4 exercised prior to tumor cell
transplant, whereas Groups 1 and 2 were sedentary during that time. Immediately after
transplant, Groups 2 and 4 were running, and Groups 1 and 3 were sedentary. Tumor
growth was monitored for 18 days, and then perfusion was mapped using MRI and tumors
were removed for analysis. In a follow-up experiment, BALB/c mice were immediately
implanted with tumor cells and then randomized to running or sedentary conditions
with or without cyclophosphamide chemotherapy given one week after tumor transplant
(three 100 mg/kg doses, every other day). Tumors were again allowed to progress for
three weeks, and MRI was performed prior to tumor removal.</p><p>Animals voluntarily
ran 5-6 km per day prior to transplant and 4-5 km per day after transplant. Body weight
was unaffected by exercise. Voluntary wheel running reduced tumor growth rate nearly
twofold and significantly increased apoptosis. Additionally, running after tumor implantation
caused significant increases in microvessel density (CD31) and vessel maturity (colocalization
of CD31 with NG2 and desmin). Hypoxia (EF5) was significantly reduced in the exercising
animals, and MRI showed that tumors were more uniformly perfused in the running groups.
Furthermore, exercise significantly enhanced the effectiveness of cyclophosphamide
in slowing tumor growth. Taken together, these results suggest that aerobic exercise
slows breast tumor growth, improves tumor vessel structure and function, and augments
the effectiveness of cyclophosphamide chemotherapy. </p><p>These findings have important
implications for the use of exercise in cancer treatment. Using a clinically relevant
animal model, we provide the first conclusive evidence that exercise may do more than
decrease symptoms and improve quality of life for cancer patients. Our data suggest
that exercise may, in fact, be an effective anti-tumor intervention both alone and
in combination with other cytotoxic therapies.</p>
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