Hyperglycemia-Induced miR-467 Drives Tumor Inflammation and Growth in Breast Cancer.

Jasmine Gajeton,Olga Stenina-Adognravi,Santoshi Muppala,Jessica Zhang,Dmitriy Verbovetskiy,Irene Krukovets

doi:10.3390/cancers13061346

Jasmine Gajeton, Olga Stenina-Adognravi + Show 4 more

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https://doi.org/10.3390/cancers13061346

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Journal: Cancers	Publication Date: Mar 16, 2021
Citations: 15	License type: CC BY 4.0

Affiliation: Cleveland Clinic, Case Western Reserve University

Abstract

The tumor microenvironment contains the parenchyma, blood vessels, and infiltrating immune cells, including tumor-associated macrophages (TAMs). TAMs affect the developing tumor and drive cancer inflammation. We used mouse models of hyperglycemia and cancer and specimens from hyperglycemic breast cancer (BC) patients to demonstrate that miR-467 mediates the effects of high blood glucose on cancer inflammation and growth. Hyperglycemic patients have a higher risk of developing breast cancer. We have identified a novel miRNA-dependent pathway activated by hyperglycemia that promotes BC angiogenesis and inflammation supporting BC growth. miR-467 is upregulated in endothelial cells (EC), macrophages, BC cells, and in BC tumors. A target of miR-467, thrombospondin-1 (TSP-1), inhibits angiogenesis and promotes resolution of inflammation. Systemic injections of a miR-467 antagonist in mouse models of hyperglycemia resulted in decreased BC growth (p < 0.001). Tumors from hyperglycemic mice had a two-fold increase in macrophage accumulation compared to normoglycemic controls (p < 0.001), and TAM infiltration was prevented by the miR-467 antagonist (p < 0.001). BC specimens from hyperglycemic patients had increased miR-467 levels, increased angiogenesis, decreased levels of TSP-1, and increased TAM infiltration in malignant breast tissue in hyperglycemic vs. normoglycemic patients (2.17-fold, p = 0.002) and even in normal breast tissue from hyperglycemic patients (2.18-fold increase, p = 0.04). In malignant BC tissue, miR-467 levels were upregulated 258-fold in hyperglycemic patients compared to normoglycemic patients (p < 0.001) and increased 56-fold in adjacent normal tissue (p = 0.008). Our results suggest that miR-467 accelerates tumor growth by inducing angiogenesis and promoting the recruitment of TAMs to drive hyperglycemia-induced cancer inflammation.

Highlights

In the US, breast cancer (BC) is the most common cancer diagnosis in post-menopausal women and is the second leading cause of cancer deaths [1]
We have recently found that miR-467 is upregulated by high glucose in cultured macrophages [26]
In three different mouse models of hyperglycemia, BC growth was accelerated by the high glucose levels (Figure 1)

Summary

Introduction

In the US, breast cancer (BC) is the most common cancer diagnosis in post-menopausal women and is the second leading cause of cancer deaths [1]. Chronic inflammation is characteristic of obese and T2D patients, and present in mammary tissue in the majority of obese individuals [7,8,9,10]. This creates an interesting interaction between macrophages and adipocytes and may be important in understanding BC progression [11,12]. Primary tumors secrete cytokines, such as CCL2, to recruit blood monocytes into the tumor and sustain chronic inflammation There, they differentiate into tumor-associated macrophages (TAMs) and shift the milieu to support tumor growth [7,12]. The increased infiltration of TAMs has a strong correlation with a poor prognosis [15,16]

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