Effect of aerobic exercise on tumor physiology in an animal model of human breast cancer

Jones, Lee W.; Viglianti, Benjamin L.; Tashjian, Jessica A.; Kothadia, Sejal; Keir, Stephen T.; Freedland, Stephen J.; Potter, Michael Q.; Moon, Eui Jung; Schroeder, Thies; Herndon, James E.; Dewhirst, Mark W.

doi:10.1152/japplphysiol.00424.2009

Cited by 113 publications

(131 citation statements)

References 39 publications

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“…In recent years, regular exercise has been demonstrated to considerably lead to inhibition of tumor growth and mitigation of metastatic expansion in animals and humans (25)(26)(27). In the present study, the tumor volume and tumor growth rate was decreased in the endurance training group, such that in the 10th week, tumor volume growth was 10.34 times greater than the first week, while in the control group, the corresponding rate was 12.13 times.…”

Section: Discussionsupporting

confidence: 45%

Endurance Training Attenuates Angiogenesis Following Breast Cancer by Regulation of MiR-126 and MiR-296 in Breast Cancer Bearing Mice

2017

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Background: In recent decades, various studies have shown a relationship between exercise and decreased mortality in patients with breast cancer. However, potentially involved molecular mechanisms are yet to be detected. Objectives: The goal of this study was to investigate the effect of endurance training on gene expression of miR-126, miR-296, HGS and protein expression of VEGF-A, in the tumor tissues of breast cancer bearing mice.

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Section: Discussionsupporting

confidence: 45%

Endurance Training Attenuates Angiogenesis Following Breast Cancer by Regulation of MiR-126 and MiR-296 in Breast Cancer Bearing Mice

2017

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“…Given that exercise is associated with increased cardiac output and regional changes in blood flow, the bioavailability of DOX to the tumor environment may have improved the potency of the drug. Jones et al found intratumoral vascularization increased in tumors taken from exercised mice compared with tumors from sedentary mice (22). Another possibility is that soluble factors found in plasma following exercise may inhibit tumor cell survival and proliferation.…”

Section: Discussionmentioning

confidence: 99%

Concomitant low-dose doxorubicin treatment and exercise

Sturgeon

Schadler

Muthukumaran

et al. 2014

American Journal of Physiology-Regulatory, Integrative and Comp

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Cardiotoxicity is a side effect for cancer patients treated with doxorubicin (DOX). We tested the hypothesis that low-intensity aerobic exercise concomitant with DOX treatment would offset DOX-induced cardiotoxicity while also improving the therapeutic efficacy of DOX on tumor progression. B16F10 melanoma cells (3 ϫ 10 5 ) were injected subcutaneously into the scruff of 6-to 8-wk-old male C57BL/6 mice (n ϭ 48). A 4 mg/kg cumulative dose of DOX was administered over 2 wk, and exercise (EX) consisted of treadmill walking (10 m/min, 45 min/day, 5 days/ wk, 2 wk). Four experimental groups were tested: 1) sedentary (SED) ϩ vehicle, 2) SED ϩ DOX, 3) EX ϩ vehicle, and 4) EX ϩ DOX. Tumor volume was attenuated in DOX and lowest in EX ϩ DOX. DOX-treated animals had less gain in body weight, reduced heart weights (HW), smaller HW-to-body weight ratios, and shorter tibial lengths by the end of the protocol; and exercise did not reverse the cardiotoxic effects of DOX. Despite decreased left ventricular (LV) mass with DOX, cardiomyocyte cross-sectional area, ␤-myosin heavy chain gene expression, and whole heart systolic (fractional shortening) and diastolic (E/A ratio) function were similar among groups. DOX also resulted in increased LV fibrosis with lower LV end diastolic volume and stroke volume. Myocardial protein kinase B activity was increased with both DOX and EX treatments, and tuberous sclerosis 2 (TSC2) abundance was reduced with EX. Downstream phosphorylation of TSC2 and mammalian target of rapamycin were similar across groups. We conclude that exercise increases the efficacy of DOX in inhibiting tumor growth without mitigating subclinical DOXinduced cardiotoxicity in a murine model of melanoma. neoplasm; drug therapy; cardiotoxicity; heart DOXORUBICIN (DOX) is an anthracycline with broad clinical application across the cancer spectrum as an effective antineoplastic agent (14, 30). However, progressive and dose-dependent early and late-onset cardiotoxicity limits the clinical efficacy of DOX (9). Acute cardiotoxicity is associated with arrhythmias and transient left ventricular (LV) dysfunction, whereas late-onset cardiomyopathy, which can occur up to 15 years after DOX administration, can manifest with overt LV dysfunction and heart failure (35). This is a significant clinical issue given cancer survivors already face a 15-fold increased rate of heart failure (27).There are numerous transcriptional and posttranslational pathophysiological mechanisms associated with DOX-induced cardiotoxicity, including increased generation of reactive oxygen species and lipid peroxidation, mitochondrial damage, DNA damage, reduction in protein synthesis, increased apoptosis, and alterations in ␤-adrenergic signaling and Ca 2ϩ handling (28). A recent study also showed that DOX caused nearly full extinction of competent cardiac progenitor cells. Subsequent intramyocardial injections of syngeneic cardiac progenitors rescued the heart from DOX-induced cardiotoxicity (7). These data suggest that a reduction in cardiomyocyte cell number...

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“…In support of our findings, several other investigations have also shown benefits of physical activity on breast cancer independent of changes in body composition (5,9,10). Therefore, additional hypotheses explaining the changes induced by voluntary wheel running may include alterations in energy sensing pathways, growth related proteins and/or myokines and cytokines (14,15,31). In fact, we have previously shown that treadmill exercise can reduce circulating levels of the inflammatory, pro-tumorigenic cytokines, MCP-1 and IL-6, in accordance with decreased tumor volume in C3(1)/SV40Tag mice (15).…”

Section: Discussionmentioning

confidence: 96%

“…Thompson et al (26) has consistently shown decreased carcinogenic incidence after both free and motorized wheel running in the chemicallyinduced rat model of mammary tumorigenesis (20,24,26). Conversely, benefits as well as no effect of exercise have been reported in mouse implantation models using MDA-MB-231 human breast cancer cells (14,25). However, chemical, implantation and hormone-induced cancer models may not accurately portray the development and progression of the human disease making it difficult to specifically assess the effects of exercise on disease initiation and progression.…”

Section: Discussionmentioning

confidence: 99%

“…Numerous animal studies have investigated the relationship between physical activity and reductions in mammary tumor growth and development; however, conflicting findings have weakened the basis for inferring a causal relationship. For example, many have reported benefits of exercise on mammary growth and development (5-10) while others have reported either no effect or negative outcomes (11)(12)(13)(14). The disparate results are likely due to the variability in animal models as well as differences across exercise protocols in which intensity, mode and duration often vary making it difficult to compare across studies.…”

Section: Introductionmentioning

confidence: 99%

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Effects of voluntary exercise on tumorigenesis in the C3(1)/SV40Tag transgenic mouse model of breast cancer

Steiner

Davis

McClellan

et al. 2013

International Journal of Oncology

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Abstract. Epidemiologic studies suggest an association between physical activity (PA) and breast cancer risk. We examined the relationship between voluntary wheel running and breast cancer in C3(1)/SV40Tag mice. Female FVB/N and C3(1)/SV40Tag mice were assigned to either PA [C3(1)-PA] (n=12) or sedentary (Sed) [C3(1)-Sed] (n=15) treatment and were placed in a cage with access to a running wheel (PA) or without (Sed) from 4 to 24 weeks of age (sacrifice). Physical activity data were analyzed for running distance, time and speed. Body composition was examined at 12 weeks of age. Tumors were counted twice weekly and at sacrifice to assess multiplicity. Tumor volume was calculated using external calipers [0.52 x (largest diameter) x (smallest diameter) 2 ]. Heart and body weight were also recorded at sacrifice. Results showed that voluntary wheel running reduced tumor volume per tumor [C3(1)-Sed, 422.3±89.9 mm 3 ; C3(1)-PA, 260.2±61.7 mm 3 ] (P<0.05), but was associated with increased tumor number (P<0.05). Body composition analysis showed no differences in body fat between the groups. Heart weight/body weight ratio was increased following physical activity (P<0.05) providing evidence of a training effect. In conclusion, voluntary wheel running activity was effective at slowing tumor growth in the C3(1)/SV40Tag mouse model of breast cancer, but did not inhibit tumor initiation. These data provide support for further development of the C3(1)/SV40Tag mouse model for use in understanding the role of physical activity on breast cancer progression and the mechanisms for its effects.

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Effect of aerobic exercise on tumor physiology in an animal model of human breast cancer

Abstract: JE 2nd, Dewhirst MW. Effect of aerobic exercise on tumor physiology in an animal model of human breast cancer.

Cited by 113 publications

References 39 publications

Endurance Training Attenuates Angiogenesis Following Breast Cancer by Regulation of MiR-126 and MiR-296 in Breast Cancer Bearing Mice

Endurance Training Attenuates Angiogenesis Following Breast Cancer by Regulation of MiR-126 and MiR-296 in Breast Cancer Bearing Mice

Concomitant low-dose doxorubicin treatment and exercise

Effects of voluntary exercise on tumorigenesis in the C3(1)/SV40Tag transgenic mouse model of breast cancer

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