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Research article
Olga Stenina-Adognravi
Cleveland Clinic
Corresponding Author
ORCiD: https://orcid.org/0000-0002-1256-0545
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: 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.
Methods: 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.
Results: Hyperglycemic patients have a higher risk of developing breast cancer (BC). 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<.001). Tumors from hyperglycemic mice had a 2-fold increase in macrophage accumulation compared to normoglycemic controls (P<.001), and TAM infiltration was prevented by the miR-467 antagonist (P<.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=.002) and even in normal breast tissue from hyperglycemic patients (2.18-fold inc., P=.04). In malignant BC tissue, miR-467 levels were upregulated 258-fold in hyperglycemic patients compared to normoglycemic patients (P<.001) and increased 56-fold in adjacent normal tissue (P=.008).
Conclusions: Our results suggest that miR-467 accelerates tumor growth by inducing angiogenesis and promoting the recruitment of TAMs to drive hyperglycemia-induced cancer inflammation.
Keywords
miRNA, tumor-associated macrophages, breast cancer, hyperglycemia
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A new preprint design is coming!
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This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Research article
Olga Stenina-Adognravi
Cleveland Clinic
Corresponding Author
ORCiD: https://orcid.org/0000-0002-1256-0545
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
View the published article at Cancers.
Version 1
Posted 17 Aug, 2020
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Cancers.
Background: 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.
Methods: 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.
Results: Hyperglycemic patients have a higher risk of developing breast cancer (BC). 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<.001). Tumors from hyperglycemic mice had a 2-fold increase in macrophage accumulation compared to normoglycemic controls (P<.001), and TAM infiltration was prevented by the miR-467 antagonist (P<.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=.002) and even in normal breast tissue from hyperglycemic patients (2.18-fold inc., P=.04). In malignant BC tissue, miR-467 levels were upregulated 258-fold in hyperglycemic patients compared to normoglycemic patients (P<.001) and increased 56-fold in adjacent normal tissue (P=.008).
Conclusions: Our results suggest that miR-467 accelerates tumor growth by inducing angiogenesis and promoting the recruitment of TAMs to drive hyperglycemia-induced cancer inflammation.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
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