Long-term exercise training as a modulator of mammary cancer vascularization

Abstract

Background: Breast cancer remains a leading cause of death by cancer worldwide. It is commonly accepted that angiogenesis and the expression of angiogenic factors such as vascular endothelial growth factor-A (VEGF-A) is associated with the increased risk of metastasis and poor patient outcome.Objective: This work aimed to evaluate the effects of long-term exercise training on the growth and vascularization of mammary tumors in a rat model. Materials and methods:Fifty female Sprague-Dawley rats were divided into four groups: two N-methyl-N-nitrosourea (MNU)-exposed groups (exercised and sedentary) and two control groups (exercised and sedentary). MNU was administered once, intraperitoneally at 7 weeks-old. Animals were then exercised on a treadmill for 35 weeks. Mammary tumors were evaluated using thermography, ultrasonography [Power Doppler (PDI), B Flow and contrast-enhanced ultrasound (CEUS)], and immunohistochemistry (VEGF-A).Results: Both, MNU sedentary and exercised groups showed 100% of tumor incidence, but exercised animals showed less tumors with an increased latency period. Exercise training also enhanced VEGF-A immunoexpression and vascularization (microvessel density, MVD) (p < 0.05), and reduced histological aggressiveness. Ultrasound and 2 -thermal imaging analysis confirmed the enhanced vascularization of tumors on exercised animals.Conclusion: Long-term exercise training increased VEGF-A expression, leading to enhanced tumor vascularization and reduced tumor burden, multiplicity and histological aggressiveness.

A Contrast‐Enhanced Ultrasonographic Study About the Impact of Long‐term Exercise Training on Mammary Tumor Vascularization

“…The vascularization of the mammary tumors used in this study was previously evaluated by thermography, US (power Doppler and B‐flow modes), and immunohistochemistry using vascular endothelial growth factor A immunoexpression and quantification of microvessel density. Data from all techniques suggested higher vascularization of mammary tumors in the MNU exercised group compared with mammary tumors in the MNU sedentary one …”

“…Data from all techniques suggested higher vascularization of mammary tumors in the MNU exercised group compared with mammary tumors in the MNU sedentary one. 19,20 Although immunohistochemistry and microvessel density analysis are considered reference standards for assessment of tumor vascularization, they are invasive techniques that can be performed only after excision of tumors and do not allow an evaluation of angiogenesis at different times throughout an experimental protocol. 25 Additionally, immunohistochemistry is not reproducible (because of distinct laboratory conditions, antibodies, and antigen retrieval), and the evaluation is relatively subjective, 2-dimensional, and not necessarily representative of vascularity throughout the entire sample.…”

“…At the end of the protocol, all surviving animals (42 weeks of age) were anesthetized with ketamine (75 mg/kg; Imalgene 1000; Merial SAS, Lyon, France) and xylazine (10 mg/kg; Rompun 2%; Bayer Healthcare SA, Kiel, Germany), and the mammary tumor vascularization was evaluated by US (power Doppler, B‐flow, pulsed Doppler, and contrast‐enhanced US). The power Doppler and B‐flow analyses were performed as previously described by our research team using a real‐time scanner (LOGIQ P6; GE Healthcare, Milwaukee, WI) and a 10‐MHz linear transducer . The pulsatility index (PI) and resistive index (RI) were determined on pulsed Doppler images by means of the equipment's autotrace software function by the following formulas: PI = (peak systolic velocity – end‐diastolic velocity)/mean velocity; and RI = (peak systolic velocity – end‐diastolic velocity)/peak systolic velocity.…”

“…The power Doppler and B-flow analyses were performed as previously described by our research team using a real-time scanner (LOGIQ P6; GE Healthcare, Milwaukee, WI) and a 10-MHz linear transducer. 19,20 The pulsatility index (PI) and resistive index (RI) were determined on pulsed Doppler images by means of the equipment's autotrace software function by the following formulas 21 : PI 5 (peak systolic velocity -end-diastolic velocity)/ mean velocity; and RI 5 (peak systolic velocity -enddiastolic velocity)/peak systolic velocity.…”

The Impact of Exercise Training on Breast Cancer

“…Malicka et al demonstrated that moderate intensity training reduced the number of induced tumors in rats (4). Other studies showed that in animals physically active at puberty (rodent treadmill, tunnels and ladders), the risk of developing the disease is decreased, the possible tumor development is delayed and smaller-sized tumors are observed (5)(6)(7)(8)(9)(10)(11). Currently, a longer survival time is observed in individuals after cancer treatment who regularly exercise (12)(13)(14)(15)(16)(17) (23,24).…”