Introduction
Methods
Eligibility criteria
Search strategy and study selection
Outcome measures and data extraction
Quality assessment
Statistical analysis
Results
Study selection
Study and participant characteristics
Variable | Preclinical trials (n = 17) | Clinical trials (n = 1) |
---|---|---|
Publication year | ||
2000–2009 | 1 (6) | 0 (0) |
2010–2021 | 16 (94) | 1 (100) |
Sample size | ||
≤20 | 7 (41) | 1 (100) |
21–49 | 7 (41) | 0 (0) |
≥50 | 3 (18) | 0 (0) |
Study duration | ||
<3 weeks | 7 (41) | 0 (0) |
3–8 weeks | 8 (47) | 0 (0) |
>8 weeks | 2 (12) | 1 (100) |
Animal speciesa | ||
Mice | 14 (82) | – |
Rat | 4 (24) | – |
Animal breed/strain | ||
BALB/c mice | 5 (29) | – |
Nude micea | 3 (18) | – |
C57BL/6 mice | 3 (18) | – |
Sprague-Dawley rat | 2 (12) | – |
Athymic mice | 2 (12) | – |
ApoE−/− mice | 1 (6) | – |
Copenhagen ratsa | 1 (6) | – |
American Cancer Institute rats | 1 (6) | – |
Cancer type | ||
Breastb | 9 (53) | 1 (100) |
Prostate | 3 (18) | 0 (0) |
Pancreaticb | 2 (12) | 0 (0) |
Melanomab | 2 (12) | 0 (0) |
Ewing sarcomab | 1 (6) | 0 (0) |
Liver | 1 (6) | 0 (0) |
Lymphatic | 1 (6) | 0 (0) |
Exercise mode | ||
Type | ||
Treadmill running | 11 (65) | 0 (0) |
Wheel running | 6 (35) | 0 (0) |
Cycling | 0 (0) | 1 (100) |
Frequencyc | ||
1–4×/week | 1 (6) | 1 (100) |
5–7×/week | 17 (100) | 0 (0) |
Outcome measured | ||
Hypoxia | 10 (59) | 1 (100) |
Vascularisation | 14 (82) | 1 (100) |
Blood flow | 6 (35) | 1 (100) |
Risk of bias
Preclinical: SYRCLE Risk of Bias
Clinical: Cochrane Risk of Bias
Author (year) | Participants | Housing condition | Cancer type/model | Intervention | Outcome measure: method of measure | Author reported result | Other comments |
---|---|---|---|---|---|---|---|
Preclinical studies | |||||||
Betof et al. (2015) | N = 22–24 female immunocompetent BALB/c mice | Housing groups: control group were housed individually; experimental group not reported Temperature: not reported Humidity: not reported Light/dark cycle: mice exercised in the dark cycle Wheel diameter: 11.5 cm | Breast: syngeneic 4T1 murine breast cancer cells orthotopically transplanted in the dorsal mammary fat pad | Mode: voluntary wheel running Frequency: continuous access to 11.5 cm diameter wheel Duration: 18 days Speed/distance: not reported | Hypoxia: EF5 Vascularisation: MVD by CD31, vascular maturity Blood flow: Perfusion by magnetic resonance imaging (MRI) | Hypoxia: ↓ Vascularisation: ↑ MVD ↑ vessel maturity Blood flow: ↑ | |
Buss et al. (2018) | N = 30–43 female ApoE+/− mice | Housing groups: control group were housed in pairs or threes; experimental group were housed in pairs Temperature: ~22°C Humidity: not reported Light/dark cycle: housed in 12:12-h light/dark cycle Wheel diameter: not reported | Breast: syngeneic EO771 murine medullary breast adenocarcinoma implanted orthotopically into the 4th mammary fat pad | Mode: voluntary wheel running Frequency: continuous wheel access Duration: until tumours reached 600 m3 (~17 days) Distance: 10 km/day per pair | Hypoxia: Pimonidazole Vascularisation: MVD by CD31 Blood flow: perfusion by Hoechst 33342 staining | Hypoxia: ↔ Vascularisation: ↔ Blood flow: ↔ | Mice were euthanised early if impact on welfare occurred due to ulceration of the tumour (n =8) or suspicion of internal tumours (n=5). One mouse was euthanised before the tumour reached measurable size due to malocclusion. |
Buss et al. (2018) | N = 30–43 female ApoE+/− mice | Housing groups: control group were housed in pairs or threes; experimental group were housed in pairs Temperature: ~22°C Humidity: not reported Light/dark cycle: housed in 12:12-h light/dark cycle Wheel diameter: not reported | Breast: syngeneic EO771 murine medullary breast adenocarcinoma implanted orthotopically into the 4th mammary fat pad | Mode: voluntary wheel running Frequency: wheel access every 2nd day Duration: until tumours reached 600 m3 (~17 days) Distance: 8 km/day per pair | Hypoxia: pimonidazole Vascularisation: MVD by CD31 Blood flow: Pperfusion by Hoechst 33342 staining | Hypoxia: ↔ Vascularisation: ↔ Blood flow: ↔ | Mice were euthanised early if impact on welfare occurred due to ulceration of the tumour (n =8) or suspicion of internal tumours (n = 5). One mouse was euthanised before the tumour reached measurable size due to malocclusion. |
Buss et al. (2020) | N = 48 C57BL/6 female mice | Housing groups: housed in pairs Temperature: not reported Humidity: not reported Light/dark cycle: housed in 12:12-h light/dark cycle Wheel diameter: not reported | Melenoma and breast: B16-F10 melanoma cells or EO771 breast cells injected subcutaneously into the flank or mammary fat pad | Mode: voluntary wheel running Frequency: continuous access to wheel Duration: until melanoma tumours reached 1000 m3 (median 17 days) or breast tumours reached 600 m3 (median 21 days) Distance: 8 km/day | Hypoxia: pimonidazole Vascularisation: MVD by CD31 Blood flow: perfusion by Hoechst 33342 staining | Hypoxia: ↔ Vascularisation: ↔ Blood flow: ↔ | |
Dufresne et al. (2020) | N = 17 athymic male nude mice | Housing groups: not reported Temperature: not reported Humidity: not reported Light/dark cycle: housed in 12:12-h light/dark cycle Stimulation for exercise: not reported | Prostate: human prostate cancer PPC-1 cells injected subcutaneously into the dorsal | Mode: treadmill running Frequency: 5×/week Duration: 25–60 min Speed: 18 m/min Slope: 10% | Vascularisation: MVD by CD31 | Vascularisation: ↔ | |
Faustino-Rocha et al. (2016) | N = 21 female Sprague-Dawley rats | Housing groups: not reported Temperature: 23 ± 2°C Humidity: 50 ± 10% Light/dark cycle: housed in 12:12-h light/dark cycled; exercised in 12-h dark cycle Stimulation for exercise: not reported | Breast: mammary tumours were induced by a single intraperitoneal administration of the carcinogen agent MNU at a dose of 50 mg/kg | Mode: treadmill running Frequency: 60 min/day for 5×/week Duration: 35 weeks Speed: not reported Slope: not reported | Vascularisation: MVD assessed visually | Vascularisation: ↑ | One animal from the MNU exercised group did not adapt to the exercise training and was excluded from the study. During the experiment nine animals died: four animals from the MNU sedentary group (MI = 27%), four animals from the MNU exercised group (MI = 29%) and one animal from the control sedentary (MI = 10%) |
Faustino-Rocha et al. (2017) | N = 21 female Sprague-Dawley rats | Housing groups: not reported Temperature: 23 ± 2°C Humidity: 50 ± 10% Light/dark cycle: housed in 12:12-h light/dark cycled; exercised in 12-h dark cycle Stimulation for exercise: not reported | Breast: mammary tumours were induced by a single intraperitoneal administration of the carcinogen agent MNU at a dose of 50 mg/kg | Mode: treadmill running Frequency: 60 min/day for 5×/week Duration: 35 weeks Speed: not reported Slope: not reported | Blood flow: Doppler power ultrasound | Blood flow: ↔ | One animal from the MNU exercised group did not adapt to the exercise training and was excluded from the study. During the experiment nine animals died: four animals from the MNU sedentary group (MI = 27%), four animals from the MNU exercised group (MI = 29%) and one animal from the control sedentary (MI = 10%) Due to their small size (mammary tumours <1.0 cm were not analysed), only 15 of 28 mammary tumours (54%) from the MNU sedentary group and 11 of 23 (48%) from the MNU exercised group were evaluated by contrast-enhanced US. |
Florez-Bedoya et al. (2019) | N = 10–14 male nude mice | Housing groups: not reported Temperature: not reported Humidity: not reported Light/dark cycle: not reported Stimulation for exercise: not reported | Pancreatic: patient-derived xenograft of pancreatic ductal adenocarcinoma tumour tissue implanted subcutaneously into the flank | Mode: treadmill running Frequency: 45 min/day for 5 days/week Duration: 4 weeks Speed: 12 m/min Slope: not reported | Vascularisation: MVD by CD31, functional vessels by lectin perfusion | Vascularisation: ↑ MVD ↔ functional vessels | |
Isanejad et al. (2016) | N = 16 female BALB/c mice | Housing groups: not reported Temperature: not reported Humidity: not reported Light/dark cycle: housed in 12:12-h light/dark cycle; exercised at the end of dark cycle Stimulation for exercise: gentle tap on the tail or hindquarters | Breast: mouse mammary tumour cells MC4-L2 injected into the flank | Mode: treadmill running Frequency: 10–14 min/day for 5 days/week Duration: 5 weeks Speed: 16–18 m/min that increased each week Slope: 0% Stimulus: gentle tap by investigator on the tail or hindquarters | Hypoxia: HIF1α Vascularisation: MVD by CD31 | Hypoxia: ↓ Vascularisation: ↓ | |
Jones et al. (2010) | N = 50 female athymic mice | Housing groups: housed individually Temperature: not reported Humidity: not reported Light/dark cycle: exercised in dark cycle Wheel diameter: 11.5 cm | Breast: human mammary adenocarcinoma cell line MDA-MB-231 injected orthotopically into the right dorsal mammary fat pad | Mode: voluntary wheel running Frequency: continuous access to a 11.5 cm diameter wheel Duration: until tumours reached 1500 m3 (44 ± 3 days) Distance: ~4 to ~6 km/day | Hypoxia: HIF1α and CAIX Vascularisation: MVD by CD31 Blood flow: perfusion by Hoechst 33342 staining | Hypoxia: HIF1α ↔ CAIX ↔ Vascularisation: ↔ Blood flow: ↑ | Histological analysis was only performed on tumours obtained from the 10 animals recording the highest mean exercise running distance and 10 random control animals. |
Jones et al. (2012) | N = 38 male C57BL/6 mice | Housing groups: housed individually Temperature: 21°C Humidity: 35–45% Light/dark cycle: housed in 12:12-h light/dark cycle Wheel diameter: 11.5 cm | Prostate: transgenic adenocarcinoma of mouse prostate (TRAMP) C-1 cells injected orthotopically into the prostate | Mode: voluntary wheel running Frequency: continuous access to a 11.5 cm diameter wheel Duration: four mice per group were serially killed on days 14, 31 and 36; the remaining 38 mice (exercise, n = 18; control, n = 20) were killed on day 53. Distance: ~4 to ~6 km/day | Hypoxia: HIF1α Vascularisation: MVD by CD31 Blood flow: perfusion by magnetic resonance imaging (MRI) | Hypoxia: ↑ Vascularisation: ↑ Blood flow: ↑ | |
McCullough et al. (2013) | N = 27 male Copenhagen and nude rats | Housing groups: not reported Temperature: 23°C Humidity: not reported Light/dark cycle: housed in 12:12 light/dark cycle Stimulation for exercise: not reported | Prostate: Dunning R-3327 rat prostate adenocarcinoma cell line in both animal species | Mode: treadmill running Frequency: 60 min/day for 5 days/week Duration: 7 weeks (Copenhagen rats) 5 weeks (nude rats) Speed: 15 m/min Slope: 15° | Hypoxia: EF5 and PO2 Vascularisation: patent blood vessels | Hypoxia: EF5 ↓ PO2 ↓ Vascularisation: ↔ | The duration of intervention in nude rats were shortened by 2 weeks to avoid the potential of tumour size constraints. |
Morrell et al. (2019) | N = 10–20 male nude mice | Housing groups: not reported Temperature: not reported Humidity: not reported Light/dark cycle: not reported Stimulation for exercise: not reported | Ewing Sarcoma: A673 and TC71 human Ewing Sarcoma cells injected into the backs of mice | Mode: treadmill running Frequency: 45 min/day for 5 consecutive days/week Duration: 2 weeks Speed: 12 m/min Slope: not reported | Hypoxia: HIF1α and CAIX Vascularisation: MVD by CD31, vessel morphology | Hypoxia: A673 tumours - HIF1α ↔ - CAIX↓ TC71 tumours - HIF1α ↔ - CAIX ↔ Vascularisation: ↔ MVD ↓ vessel permeability | |
Rafiei et al. (2021) | N = 16 female BALB/c mice | Housing groups: not reported Temperature: 22 ± 3°C Humidity: 40–60% Light/dark cycle: housed in 12:12-h cycle Wheel diameter: not reported | Breast: MC4-L2 cancer cells injected subcutaneously | Mode: treadmill running Frequency: 30 min in the first 2 weeks and increasing by 5 min every fortnight Duration: 8 weeks Speed: 14 m/min increasing to 20 m/min in the last 2 weeks Slope: not reported | Hypoxia: HIF1α | Hypoxia: ↓ | |
Saran et al. (2018) | N = 18 American Cancer Institute rats (sex not stated) | Housing groups: not reported Temperature: not reported Humidity: not reported Light/dark cycle: not reported Stimulation for exercise: not reported | Liver: MH-3924A cells were implanted into the liver | Mode: treadmill running Frequency: 770 m for 5 days/week Duration: 6 weeks pretumour implantation, 4 weeks posttumour implantation Speed: not reported | Vascularisation: MVD by CD31 | Vascularisation: ↓ | |
Schadler et al. (2016) | N = 10–12 male and female wild-type mice from C57B1/6J | Housing groups: not reported Temperature: not reported Humidity: not reported Light/dark cycle: not reported Stimulation for exercise: not reported | Melanoma and pancreatic: B16F10 melanoma and PDAC-4662 pancreatic ductal adenocarcinoma tumours were injected subcutaneously into the flanks of mice | Mode: treadmill running Frequency: 45 min/day for 5 consecutive days/week Duration: 3 weeks Speed: 12 m/min in mice with PDAC4662 10 m/min in mice with B16F10 Slope: not reported | Vascularisation: MVD by CD31, functional vessels by lectin, vessel length | Vascularisation: ↔ MVD ↑ vessel function ↑ vessel length | |
Wakefield et al. (2021) | N = 14 female BALB/c mice | Housing groups: housed individually Temperature: not reported Humidity: not reported Light/dark cycle: not reported Wheel diameter: not reported | Breast: EMT6 murine mammary cells were implanted into the 4th mammary | Mode: voluntary wheel running Frequency: continuous access to wheel Duration: until tumours reached 200 mm3 (15 ± 4 days) plus an additional 7 days Distance: 9–14 km/day | Hypoxia: HIF1α and HIF2α | Hypoxia: ↓ | |
Zielinski et al. (2004) | N = 137 female BALB/cByJ mice | Housing groups: housed individually Temperature: 23°C Humidity: not reported Light/dark cycle: housed in 12:12-h reverse light cycle; exercised during dark cycle Stimulation for exercise: not reported | Lymphoma: EL-4 lymphoid cells subcutaneously injected in the back behind the neck | Mode: treadmill running Frequency: 3 h or until volitional fatigue (mean time to fatigue 135 ± 25 min) for 7 days/week Duration: 5–14 days Speed: 20–40 m/min Slope: not reported | Vascularisation: MVD by CD31 | Vascularisation: ↓ | |
Clinical studies | |||||||
Jones et al. (2013) | N = 20 females | Not applicable | Breast | Mode: cycling Frequency: 45 min/day for 3 days/week Duration: 12 weeks Intensity: 55–100% VO2peak | Hypoxia: HIF1α Vascularisation: MVD by CD31, cell proliferation Blood flow: PET scan | Hypoxia: ↔ Vascularisation: ↔ MVD ↔ vessel structure Blood flow: ↓ | Results for hypoxia and vascularisation were only available for 5 participants per group. Blood flow data was limited due to technical difficulties |