Normalizing glucose levels reconfigures the mammary tumor immune and metabolic microenvironment and decreases metastatic seeding

Alsheikh, Heba Allah; Metge, Brandon J.; Ha, Chae‐Myeong; Hinshaw, Dominique C.; Mota, Mateus; Kammerud, Sarah C.; Lama-Sherpa, Tshering; Sharafeldin, Noha; Wende, Adam R.; Samant, Rajeev S.; Shevde, Lalita A.

doi:10.1016/j.canlet.2021.05.022

Cited by 13 publications

(9 citation statements)

References 81 publications

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“…The complex components of the TME nurture the surrounding environment that is essential for tumor growth. More and more studies have revealed that specific metabolic patterns of the TME potentiate tumor progression or treatment resistance [24][25][26]. Under specific conditions such as hypoxia, metabolic reprogramming occurs to enhance cellular proliferation, and cancer cells have been proven to facilitate the metabolism of reactive oxygen species, lactate, lipids, glutamine and glucose, as well as amino acids [27].…”

Section: Discussionmentioning

confidence: 99%

The Immunological Contribution of a Novel Metabolism-Related Signature to the Prognosis and Anti-Tumor Immunity in Cervical Cancer

et al. 2022

Cancers

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Cervical cancer is the most frequently diagnosed malignancy in the female reproductive system. Conventional stratification of patients based on clinicopathological characters has gradually been outpaced by a molecular profiling strategy. Our study aimed to identify a reliable metabolism-related predictive signature for the prognosis and anti-tumor immunity in cervical cancer. In this study, we extracted five metabolism-related hub genes, including ALOX12B, CA9, FAR2, F5 and TDO2, for the establishment of the risk score model. The Kaplan-Meier curve suggested that patients with a high-risk score apparently had a worse prognosis in the cervical cancer training cohort (TCGA, n = 304, p < 0.0001), validation cohort (GSE44001, n = 300, p = 0.0059) and pan-cancer cohorts (including nine TCGA tumors). Using a gene set enrichment analysis (GSEA), we observed that the model was correlated with various immune-regulation-related pathways. Furthermore, pan-cancer cohorts and immunohistochemical analysis showed that the infiltration of tumor infiltrating lymphocytes (TILs) was lower in the high-score group. Additionally, the model could also predict the prognosis of patients with cervical cancer based on the expression of immune checkpoints (ICPs) in both the discovery and validation cohorts. Our study established and validated a metabolism-related prognostic model, which might improve the accuracy of predicting the clinical outcome of patients with cervical cancer and provide guidance for personalized treatment.

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Section: Discussionmentioning

confidence: 99%

The Immunological Contribution of a Novel Metabolism-Related Signature to the Prognosis and Anti-Tumor Immunity in Cervical Cancer

et al. 2022

Cancers

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“…Manipulation of the glucosamine level didn't affect the O-GlcNAcylation level suggesting that glucose is, in fact, the master regulator of O-GlcNAcylation dysregulation in breast cancer [24]. A high glucose environment results in increased O-GlcNAcylation [37,38], confirmed in a more systemic study in which a high-glucose diet in mice led to the O-GlcNAcylation elevation [39]. Interestingly, while an extensive glucose uptake results in increased O-GlcNAcylation and OGT protein levels, it doesn't increase the mRNA level of OGT but even tends to lower it, suggesting the occurrence of a post-translation mechanism of regulation, perhaps through the OGT protein stabilization [7,2].…”

Section: Origin Of the O-glcnacylation Dysregulations In Breast Cancermentioning

confidence: 91%

Role of O-GlcNAcylation in Breast Cancer Biology

Kozal

Krześlak

2023

Cell Physiol Biochem

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Breast cancer is the most common type of cancer in women. It has been extensively researched over the past decades, but the underlying mechanisms of its growth, proliferation, invasion, and metastasis require further investigation. Dysregulation of O-GlcNAcylation which is one of the most abundant post-translational modifications, impacts on the malignant features of breast cancer. O-GlcNAcylation is broadly recognized as a nutrient sensor and participates in cells’ survival and death. Through its involvement in protein synthesis and energy metabolism, especially glucose metabolism, O-GlcNAcylation enables adaptation to a hostile environment. It supports the migration and invasion of cancer cells and may be crucial for breast cancer metastasis. This review summarizes the current state of knowledge about O-GlcNAcylation in breast cancer: the origins of its dysregulation, its effect on the different aspects of breast cancer biology, and the potential utility in diagnostics and therapy.

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“…In mammary tumor-bearing obese mice, metformin treatment reduced obesity-associated tumor growth and was associated with a marked decrease in angiogenesis within the tumor microenvironment [ 229 ]. Similarly, treatment of obese/diabetic mice with metformin during EO771 tumor growth resulted in reduced tumor growth rates with less aligned collagen, decreased vascularity, reduced numbers of CD206 + TAM, and diminished pulmonary metastasis [ 239 ]. Furthermore, treatment of ovariectomized rats with metformin decreased the growth of ERα + mammary tumors and diminished aromatase expression in CD68 + macrophages [ 240 ].…”

Section: Opportunities To Improve Therapeutic Outcomesmentioning

confidence: 99%

Breast cancer microenvironment and obesity: challenges for therapy

Hillers‐Ziemer

Kuziel

Williams

et al. 2022

Cancer Metastasis Rev

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Women with obesity who develop breast cancer have a worsened prognosis with diminished survival rates and increased rates of metastasis. Obesity is also associated with decreased breast cancer response to endocrine and chemotherapeutic treatments. Studies utilizing multiple in vivo models of obesity as well as human breast tumors have enhanced our understanding of how obesity alters the breast tumor microenvironment. Changes in the complement and function of adipocytes, adipose-derived stromal cells, immune cells, and endothelial cells and remodeling of the extracellular matrix all contribute to the rapid growth of breast tumors in the context of obesity. Interactions of these cells enhance secretion of cytokines and adipokines as well as local levels of estrogen within the breast tumor microenvironment that promote resistance to multiple therapies. In this review, we will discuss our current understanding of the impact of obesity on the breast tumor microenvironment, how obesity-induced changes in cellular interactions promote resistance to breast cancer treatments, and areas for development of treatment interventions for breast cancer patients with obesity.

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Normalizing glucose levels reconfigures the mammary tumor immune and metabolic microenvironment and decreases metastatic seeding

Cited by 13 publications

References 81 publications

The Immunological Contribution of a Novel Metabolism-Related Signature to the Prognosis and Anti-Tumor Immunity in Cervical Cancer

The Immunological Contribution of a Novel Metabolism-Related Signature to the Prognosis and Anti-Tumor Immunity in Cervical Cancer

Role of O-GlcNAcylation in Breast Cancer Biology

Breast cancer microenvironment and obesity: challenges for therapy

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