scholarly journals Physical activity modulates mononuclear phagocytes in mammary tissue and inhibits tumor growth in mice

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e10725
Author(s):  
Donald M. Lamkin ◽  
Karen P. Bradshaw ◽  
Janice Chang ◽  
Ma’ayan Epstein ◽  
Jack Gomberg ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Physical Activity ◽  
Innate Immunity ◽  
Tumor Growth ◽  
Mammary Tumor ◽  
Wheel Running ◽  
Mononuclear Phagocytes ◽  
Mammary Tissue ◽  
Gene And Protein Expression ◽  
Whole Transcriptome

The risk for breast cancer is significantly reduced in persons who engage in greater amounts of physical activity, and greater physical activity before or after diagnosis associates with reduced disease-specific mortality. Previous mechanistic studies indicate that components of innate immunity can mediate an inhibitory effect of physical activity on several types of tumor. However, in breast cancer specifically, the myeloid compartment of innate immunity is thought to exhibit high propensity for an immunosuppressive role that obstructs anti-tumor immunity. Thus, we tested the notion that greater physical activity alters mononuclear phagocytes in mammary tissue when inhibiting nascent tumor in a murine model of breast cancer. To model greater physical activity, we placed an angled running wheel in each mouse’s home cage for two weeks before tumor engraftment with EO771 mammary cancer cells that express luciferase for bioluminescent detection. Fully immunocompetent mice and mice with compromised adaptive immunity showed significantly less mammary tumor signal when given access to running wheels, although the effect size was smaller in this latter group. To investigate the role of the myeloid compartment, mononuclear phagocytes were ablated by systemic injection of clodronate liposomes at 24 h before tumor engraftment and again at the time of tumor engraftment, and this treatment reversed the inhibition in wheel running mice. However, clodronate also inhibited mammary tumor signal in sedentary mice, in conjunction with an expected decrease in gene and protein expression of the myeloid antigen, F4/80 (Adgre1), in mammary tissue. Whole transcriptome digital cytometry with CIBERSORTx was used to analyze myeloid cell populations in mammary tissue following voluntary wheel running and clodronate treatment, and this approach found significant changes in macrophage and monocyte populations. In exploratory analyses, whole transcriptome composite scores for monocytic myeloid-derived suppressor cell (M-MDSC), macrophage lactate timer, and inflammation resolution gene expression programs were significantly altered. Altogether, the results support the hypothesis that physical activity inhibits nascent mammary tumor growth by enhancing the anti-tumor potential of mononuclear phagocytes in mammary tissue.

Melatonin modifies tumor hypoxia and metabolism by inhibiting HIF-1α and energy metabolic pathway in the in vitro and in vivo models of breast cancer

2019 ◽  
Vol 2 (4) ◽  
pp. 83-98 ◽  
Author(s):  
André De Lima Mota ◽  
Bruna Vitorasso Jardim-Perassi ◽  
Tialfi Bergamin De Castro ◽  
Jucimara Colombo ◽  
Nathália Martins Sonehara ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Glucose Metabolism ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Carbonic Anhydrases ◽  
In Vivo Models ◽  
Ca Ix ◽  
Gene And Protein Expression

Breast cancer is the most common cancer among women and has a high mortality rate. Adverse conditions in the tumor microenvironment, such as hypoxia and acidosis, may exert selective pressure on the tumor, selecting subpopulations of tumor cells with advantages for survival in this environment. In this context, therapeutic agents that can modify these conditions, and consequently the intratumoral heterogeneity need to be explored. Melatonin, in addition to its physiological effects, exhibits important anti-tumor actions which may associate with modification of hypoxia and Warburg effect. In this study, we have evaluated the action of melatonin on tumor growth and tumor metabolism by different markers of hypoxia and glucose metabolism (HIF-1α, glucose transporters GLUT1 and GLUT3 and carbonic anhydrases CA-IX and CA-XII) in triple negative breast cancer model. In an in vitro study, gene and protein expressions of these markers were evaluated by quantitative real-time PCR and immunocytochemistry, respectively. The effects of melatonin were also tested in a MDA-MB-231 xenograft animal model. Results showed that melatonin treatment reduced the viability of MDA-MB-231 cells and tumor growth in Balb/c nude mice (p <0.05). The treatment significantly decreased HIF-1α gene and protein expression concomitantly with the expression of GLUT1, GLUT3, CA-IX and CA-XII (p <0.05). These results strongly suggest that melatonin down-regulates HIF-1α expression and regulates glucose metabolism in breast tumor cells, therefore, controlling hypoxia and tumor progression. 

scholarly journals IGF1 dependence of dietary energy balance effects on murine Met1 mammary tumor progression, epithelial-to-mesenchymal transition, and chemokine expression

2012 ◽  
Vol 20 (1) ◽  
pp. 39-51 ◽  
Author(s):  
Nikki A Ford ◽  
Nomeli P Nunez ◽  
Valerie B Holcomb ◽  
Stephen D Hursting
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Mammary Tumor ◽  
Murine Model ◽  
Epithelial To Mesenchymal Transition ◽  
Luminal Breast Cancer ◽  
Growth Factor Signaling ◽  
Mesenchymal Transition ◽  
Chemokine Expression ◽  
Mammary Tumor Growth

Luminal breast tumors with little or no estrogen receptor α expression confer poor prognosis. Using the Met1 murine model of luminal breast cancer, we characterized the IGF1-dependency of diet-induced obesity (DIO) and calorie restriction (CR) effects on tumor growth, growth factor signaling, epithelial-to-mesenchymal transition (EMT), and chemokine expression. Liver-specific IGF1-deficient (LID) and littermate control (LC) mice were administered control, DIO, or 30% CR diets for 3 months before orthotopic injection of Met1 cells. Tumors grew for 1 month and then were assessed for Akt pathway activation and mRNA expression of chemokine and EMT constituents. LID mice, regardless of diet, displayed reduced Met1 tumor growth and downregulated Akt, EMT, and chemokine pathways. CR, relative to control, reduced serum IGF1 and Met1 tumor growth in LC (but not LID) mice. DIO, relative to control, increased Met1 tumor growth and chemokine expression in LID mice, and had no effect on serum IGF1 or pAkt or cyclin D1 expression in either genotype. Thus, circulating IGF1 (in association with Akt, EMT, and chemokines) regulated Met1 tumor growth. While the anticancer effects of CR were largely IGF1-dependent, the procancer effects of DIO manifested only when circulating IGF1 levels were low. Thus, in a murine model of luminal breast cancer, IGF1 and its downstream signaling pathway, EMT, and chemokines present possible mechanistic regulatory targets. Transplanted MMTV1 Wnt1 mammary tumor growth was also reduced in LID mice, relative to LC mice, suggesting that the IGF1 effects on mammary tumor growth are not limited to Met1 tumors.

scholarly journals Chronic Stress Exposure Suppresses Mammary Tumor Growth and Reduces Circulating Exosome TGF-β Content via β-Adrenergic Receptor Signaling in MMTV-PyMT Mice

2020 ◽  
Vol 14 ◽  
pp. 117822342093151 ◽  
Author(s):  
Ryan P Dawes ◽  
Kathleen A Burke ◽  
Daniel K Byun ◽  
Zhou Xu ◽  
Petr Stastka ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Mammary Tumor ◽  
Adrenergic Receptor ◽  
Caspase 3 ◽  
Tumor Burden ◽  
Stress Exposure ◽  
Metastatic Lesions

Preclinical models of breast cancer have established mechanistic links between psychological stress and cancer progression. However, epidemiological evidence linking stress and cancer is equivocal. We tested the impact of stress exposure in female mice expressing the mouse mammary tumor virus polyoma middle-T antigen (MMTV-PyMT), a spontaneous model of mammary adenocarcinoma that mimics metastatic hormone receptor–positive human breast cancer development. MMTV-PyMT mice were socially isolated at 6 to 7 weeks of age during premalignant hyperplasia. To increase the potency of the stressor, singly housed mice were exposed to acute restraint stress (2 hours per day for 3 consecutive days) at 8 to 9 weeks of age during early carcinoma. Exposure to this dual stressor activated both major stress pathways, the sympathetic nervous system and hypothalamic-pituitary-adrenal axis throughout malignant transformation. Stressor exposure reduced mammary tumor burden in association with increased tumor cleaved caspase-3 expression, indicative of increased cell apoptosis. Stress exposure transiently increased tumor vascular endothelial growth factor and reduced tumor interleukin-6, but no other significant alterations in immune/inflammation-associated chemokines and cytokines or changes in myeloid cell populations were detected in tumors. No stress-induced change in second-harmonic generation-emitting collagen, indicative of a switch to a metastasis-promoting tumor extracellular matrix, was detected. Systemic indicators of slowed tumor progression included reduced myeloid-derived suppressor cell (MDSC) frequency in lung and spleen, and decreased transforming growth factor β (TGF-β) content in circulating exosomes, nanometer-sized particles associated with tumor progression. Chronic β-adrenergic receptor (β-AR) blockade with nadolol abrogated stress-induced alterations in tumor burden and cleaved caspase-3 expression, lung MDSC frequency, and exosomal TGF-β content. Despite the evidence for reduced tumor growth, metastatic lesions in the lung were not altered by stress exposure. Unexpectedly, β-blockade in nonstressed mice increased lung metastatic lesions and splenic MDSC frequency, suggesting that in MMTV-PyMT mice, β-AR activation also inhibits tumor progression in the absence of stress exposure. Together, these results suggest stress exposure can act through β-AR signaling to slow primary tumor growth in MMTV-PyMT mice.

scholarly journals Should diabetic women with breast cancer have their own intervention studies?

2011 ◽  
Vol 19 (1) ◽  
pp. C13-C17
Author(s):  
David A Potter ◽  
Douglas Yee ◽  
Zhijun Guo ◽  
Mariangellys Rodriguez
Keyword(s):  
Breast Cancer ◽  
Mouse Model ◽  
Tumor Growth ◽  
Calorie Restriction ◽  
Mammary Tumor ◽  
Intervention Studies ◽  
Diabetic Mouse ◽  
Mouse Mammary Tumor ◽  
Mammary Tumor Growth ◽  
Postmenopausal Obesity

This commentary on ‘Calorie restriction and rapamycin inhibit MMTV-Wnt-1 mammary tumor growth in a mouse model of postmenopausal obesity’ by Nogueiraet al., published in this issue ofEndocrine-Related Cancer, addresses the challenges of translating diet, exercise, and pharmacologic trials in diabetic mouse mammary tumor models to human studies. We propose that trials specifically designed to test such interventions in diabetic women with breast cancer would be valuable and informative.

scholarly journals Calorie restriction and rapamycin inhibit MMTV-Wnt-1 mammary tumor growth in a mouse model of postmenopausal obesity

2011 ◽  
Vol 19 (1) ◽  
pp. 57-68 ◽  
Author(s):  
Leticia M Nogueira ◽  
Sarah M Dunlap ◽  
Nikki A Ford ◽  
Stephen D Hursting
Keyword(s):  
Breast Cancer ◽  
Energy Balance ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Calorie Restriction ◽  
Mammary Tumor ◽  
Treadmill Exercise ◽  
Mammary Tumor Growth ◽  
Postmenopausal Obesity ◽  
Ad Libitum

Obesity is an established risk and progression factor for postmenopausal breast cancer. Interventions to decrease caloric intake and/or increase energy expenditure beneficially impact tumor progression in normoweight humans and animal models. However, despite the increasingly high global prevalence of obesity, the effects and underlying mechanisms of these energy balance modulating interventions are poorly characterized in obese individuals. The goal of this study was to better characterize the mechanism(s) responsible for the link between energy balance and breast cancer progression in the postmenopausal obesity context. We compared the effects of calorie restriction (CR), treadmill exercise (EX), and mammalian target of rapamycin (mTOR inhibitor) treatment on body composition, serum biomarkers, cellular signaling, and mammary tumor growth in obese mice. Ovariectomized C57BL/6 mice were administered a diet-induced obesity regimen for 8 weeks, then randomized into three treatment groups: control (semipurified diet fedad libitum, maintained the obese state); 30% CR (isonutrient relative to control except 30% reduction in carbohydrate calories); and EX (control diet fedad libitumplus treadmill exercise). Mice were implanted with syngeneic MMTV-Wnt-1 mammary tumor cells at week 12. Rapamycin treatment (5 mg/kg every 48 h) started at week 14. Tumors were excised at week 18. CR and rapamycin (but not EX) significantly reduced final tumor weight compared to control. In follow-up analysis, constitutive activation of mTOR ablated the inhibitory effects of CR on Wnt-1 mammary tumor growth. We conclude that mTOR inhibition may be a pharmacologic strategy to mimic the anticancer effects of CR and break the obesity–breast cancer progression link.

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