Hyperglycemia-Induced miR-467 Drives Tumor Inflammation and Growth in Breast Cancer
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 ca...
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| Format: | Article |
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MDPI AG
2021-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/6/1346 |
| _version_ | 1797541091231137792 |
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| author | Jasmine Gajeton Irene Krukovets Santoshi Muppala Dmitriy Verbovetskiy Jessica Zhang Olga Stenina-Adognravi |
| author_facet | Jasmine Gajeton Irene Krukovets Santoshi Muppala Dmitriy Verbovetskiy Jessica Zhang Olga Stenina-Adognravi |
| author_sort | Jasmine Gajeton |
| collection | DOAJ |
| description | 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 (<i>p</i> < 0.001). Tumors from hyperglycemic mice had a two-fold increase in macrophage accumulation compared to normoglycemic controls (<i>p</i> < 0.001), and TAM infiltration was prevented by the miR-467 antagonist (<i>p</i> < 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, <i>p</i> = 0.002) and even in normal breast tissue from hyperglycemic patients (2.18-fold increase, <i>p</i> = 0.04). In malignant BC tissue, miR-467 levels were upregulated 258-fold in hyperglycemic patients compared to normoglycemic patients (<i>p</i> < 0.001) and increased 56-fold in adjacent normal tissue (<i>p</i> = 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. |
| first_indexed | 2024-03-10T13:10:44Z |
| format | Article |
| id | doaj.art-0d5f80e76c064a38bcd915aac1a5a0f7 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T13:10:44Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-0d5f80e76c064a38bcd915aac1a5a0f72023-11-21T10:45:44ZengMDPI AGCancers2072-66942021-03-01136134610.3390/cancers13061346Hyperglycemia-Induced miR-467 Drives Tumor Inflammation and Growth in Breast CancerJasmine Gajeton0Irene Krukovets1Santoshi Muppala2Dmitriy Verbovetskiy3Jessica Zhang4Olga Stenina-Adognravi5Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, 9500 Euclid Avenue NB50, Cleveland, OH 44195, USADepartment of Cardiovascular and Metabolic Sciences, Cleveland Clinic, 9500 Euclid Avenue NB50, Cleveland, OH 44195, USADepartment of Cardiovascular and Metabolic Sciences, Cleveland Clinic, 9500 Euclid Avenue NB50, Cleveland, OH 44195, USADepartment of Cardiovascular and Metabolic Sciences, Cleveland Clinic, 9500 Euclid Avenue NB50, Cleveland, OH 44195, USADepartment of Cardiovascular and Metabolic Sciences, Cleveland Clinic, 9500 Euclid Avenue NB50, Cleveland, OH 44195, USADepartment of Cardiovascular and Metabolic Sciences, Cleveland Clinic, 9500 Euclid Avenue NB50, Cleveland, OH 44195, USAThe 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 (<i>p</i> < 0.001). Tumors from hyperglycemic mice had a two-fold increase in macrophage accumulation compared to normoglycemic controls (<i>p</i> < 0.001), and TAM infiltration was prevented by the miR-467 antagonist (<i>p</i> < 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, <i>p</i> = 0.002) and even in normal breast tissue from hyperglycemic patients (2.18-fold increase, <i>p</i> = 0.04). In malignant BC tissue, miR-467 levels were upregulated 258-fold in hyperglycemic patients compared to normoglycemic patients (<i>p</i> < 0.001) and increased 56-fold in adjacent normal tissue (<i>p</i> = 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.https://www.mdpi.com/2072-6694/13/6/1346miRNAtumor-associated macrophagesbreast cancerhyperglycemia |
| spellingShingle | Jasmine Gajeton Irene Krukovets Santoshi Muppala Dmitriy Verbovetskiy Jessica Zhang Olga Stenina-Adognravi Hyperglycemia-Induced miR-467 Drives Tumor Inflammation and Growth in Breast Cancer Cancers miRNA tumor-associated macrophages breast cancer hyperglycemia |
| title | Hyperglycemia-Induced miR-467 Drives Tumor Inflammation and Growth in Breast Cancer |
| title_full | Hyperglycemia-Induced miR-467 Drives Tumor Inflammation and Growth in Breast Cancer |
| title_fullStr | Hyperglycemia-Induced miR-467 Drives Tumor Inflammation and Growth in Breast Cancer |
| title_full_unstemmed | Hyperglycemia-Induced miR-467 Drives Tumor Inflammation and Growth in Breast Cancer |
| title_short | Hyperglycemia-Induced miR-467 Drives Tumor Inflammation and Growth in Breast Cancer |
| title_sort | hyperglycemia induced mir 467 drives tumor inflammation and growth in breast cancer |
| topic | miRNA tumor-associated macrophages breast cancer hyperglycemia |
| url | https://www.mdpi.com/2072-6694/13/6/1346 |
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