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Lactate Metabolism in Breast Cancer Microenvironment: Contribution Focused on Associated Adipose Tissue and Obesity.

ABSTRACT: Metabolic reprogramming that favors high glycolytic flux with lactate production in normoxia is among cancer hallmarks. Lactate is an essential oncometabolite regulating cellular redox homeostasis, energy substrate partitioning, and intracellular signaling. Moreover, malignant phenotype's chief characteristics are dependent on the interaction between cancer cells and their microenvironment. In breast cancer, mammary adipocytes represent an essential cellular component of the tumor milieu. We analyzed lactate concentration, lactate dehydrogenase (LDH) activity, and isozyme pattern, and LDHA/LDHB protein expression and tissue localization in paired biopsies of breast cancer tissue and cancer-associated adipose tissue in normal-weight and overweight/obese premenopausal women, compared to benign breast tumor tissue and adipose tissue in normal-weight and overweight/obese premenopausal women. We show that higher lactate concentration in cancer tissue is concomitant with a shift in isozyme pattern towards the "muscle-type" LDH and corresponding LDHA and LDHB protein expression changes. In contrast, significantly higher LDH activity in cancer-associated adipose tissue seems to be directed towards lactate oxidation. Moreover, localization patterns of LDH isoforms varied substantially across different areas of breast cancer tissue. Invasive front of the tumor showed cell-specific protein localization of LDHA in breast cancer cells and LDHB in cancer-associated adipocytes. The results suggest a specific, lactate-centric relationship between cancer tissue and cancer-associated adipose tissue and indicate how cancer-adipose tissue cross-talk may be influenced by obesity in premenopausal women.

SUBMITTER: Kalezic A

PROVIDER: S-EPMC7766866 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Lactate Metabolism in Breast Cancer Microenvironment: Contribution Focused on Associated Adipose Tissue and Obesity.

Kalezic Andjelika A Udicki Mirjana M Srdic Galic Biljana B Aleksic Marija M Korac Aleksandra A Jankovic Aleksandra A Korac Bato B

International journal of molecular sciences 20201218 24

Metabolic reprogramming that favors high glycolytic flux with lactate production in normoxia is among cancer hallmarks. Lactate is an essential oncometabolite regulating cellular redox homeostasis, energy substrate partitioning, and intracellular signaling. Moreover, malignant phenotype's chief characteristics are dependent on the interaction between cancer cells and their microenvironment. In breast cancer, mammary adipocytes represent an essential cellular component of the tumor milieu. We ana ...[more]

PMID: 33353120

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Project description:BackgroundObesity-related cardiovascular risk, end points, and mortality are strongly related to arterial stiffening. Current therapeutic approaches for arterial stiffening are not focused on direct targeting within the vessel. Perivascular adipose tissue (PVAT) surrounding the artery has been shown to modulate vascular function and inflammation. Peroxisome proliferator-activated receptor γ (PPARγ) activation significantly decreases arterial stiffness and inflammation in diabetic patients with coronary artery disease. Thus, we hypothesized that PPARγ activation alters the PVAT microenvironment, thereby creating a favorable environment for the attenuation of arterial stiffening in obesity.MethodsObese ob/ob mice were used to investigate the effect of PPARγ activation on the attenuation of arterial stiffening. Various cell types, including macrophages, fibroblasts, adipocytes, and vascular smooth muscle cells, were used to test the inhibitory effect of pioglitazone, a PPARγ agonist, on the expression of elastolytic enzymes.ResultsPPARγ activation by pioglitazone effectively attenuated arterial stiffening in ob/ob mice. This beneficial effect was not associated with the repartitioning of fat from or changes in the browning of the PVAT depot but was strongly related to improvement of the PVAT microenvironment, as evidenced by reduction in the expression of pro-inflammatory and pro-oxidative factors. Pioglitazone treatment attenuated obesity-induced elastin fiber fragmentation and elastolytic activity and ameliorated the obesity-induced upregulation of cathepsin S and metalloproteinase 12, predominantly in the PVAT. In vitro, pioglitazone downregulated Ctss and Mmp12 in macrophages, fibroblasts, and adipocytes-cell types residing within the adventitia and PVAT. Ultimately, several PPARγ binding sites were found in Ctss and Mmp12 in Raw 264.7 and 3T3-L1 cells, suggesting a direct regulatory mechanism by which PPARγ activation repressed the expression of Ctss and Mmp-12 in macrophages and fibroblasts.ConclusionsPPARγ activation attenuated obesity-induced arterial stiffening and reduced the inflammatory and oxidative status of PVAT. The improvement of the PVAT microenvironment further contributed to the amelioration of elastin fiber fragmentation, elastolytic activity, and upregulated expression of Ctss and Mmp12. Our data highlight the PVAT microenvironment as an important target against arterial stiffening in obesity and provide a novel strategy for the potential clinical use of PPARγ agonists as a therapeutic against arterial stiffness through modulation of PVAT function.

Dataset Information

Lactate Metabolism in Breast Cancer Microenvironment: Contribution Focused on Associated Adipose Tissue and Obesity.

Publications

Lactate Metabolism in Breast Cancer Microenvironment: Contribution Focused on Associated Adipose Tissue and Obesity.

Similar Datasets

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