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J Clin Invest. 2019 Mar 11;130:1654-1670. doi: 10.1172/JCI123106. eCollection 2019 Mar 11.

Endothelial miR-30c suppresses tumor growth via inhibition of TGF-β-induced Serpine1.

Author information

1
Department of Cell Biology and Physiology, University of North Carolina (UNC) at Chapel Hill, Chapel Hill, North Carolina, USA.
2
Children's Cancer Institute, Kensington, New South Wales, Australia.
3
Department of Microbiology, Immunology, and Cancer Biology, The University of Virginia, Charlottesville, Virginia, USA.
4
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT).
5
Department of Chemical Engineering.
6
Harvard-MIT Division of Health Sciences and Technology, and.
7
Institute for Medical Engineering and Science, MIT, Cambridge, Massachusetts, USA.
8
Lineberger Comprehensive Cancer Center.
9
School of Medicine.
10
Department of Genetics, and.
11
Department of Pathology and Laboratory Medicine, UNC McAllister Heart Institute, UNC at Chapel Hill, Chapel Hill, North Carolina, USA.
12
Department of Public Health Sciences, and.
13
Bioinformatics Core, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
14
Department of Medicine, Division of Hematology and Oncology, UNC McAllister Heart Institute, UNC at Chapel Hill, Chapel Hill, North Carolina, USA.
15
Emily Couric Cancer Center, The University of Virginia, Charlottesville, Virginia, USA.

Abstract

In tumors, extravascular fibrin forms provisional scaffolds for endothelial cell (EC) growth and motility during angiogenesis. We report that fibrin-mediated angiogenesis was inhibited and tumor growth delayed following postnatal deletion of Tgfbr2 in the endothelium of Cdh5-CreERT2 Tgfbr2fl/fl mice (Tgfbr2iECKO mice). ECs from Tgfbr2iECKO mice failed to upregulate the fibrinolysis inhibitor plasminogen activator inhibitor 1 (Serpine1, also known as PAI-1), due in part to uncoupled TGF-β-mediated suppression of miR-30c. Bypassing TGF-β signaling with vascular tropic nanoparticles that deliver miR-30c antagomiRs promoted PAI-1-dependent tumor growth and increased fibrin abundance, whereas miR-30c mimics inhibited tumor growth and promoted vascular-directed fibrinolysis in vivo. Using single-cell RNA-Seq and a NanoString miRNA array, we also found that subtypes of ECs in tumors showed spectrums of Serpine1 and miR-30c expression levels, suggesting functional diversity in ECs at the level of individual cells; indeed, fresh EC isolates from lung and mammary tumor models had differential abilities to degrade fibrin and launch new vessel sprouts, a finding that was linked to their inverse expression patterns of miR-30c and Serpine1 (i.e., miR-30chi Serpine1lo ECs were poorly angiogenic and miR-30clo Serpine1hi ECs were highly angiogenic). Thus, by balancing Serpine1 expression in ECs downstream of TGF-β, miR-30c functions as a tumor suppressor in the tumor microenvironment through its ability to promote fibrin degradation and inhibit blood vessel formation.

KEYWORDS:

Breast cancer; Extracellular matrix; Oncology; Vascular Biology; endothelial cells

PMID:
30855280
PMCID:
PMC6436861
[Available on 2019-07-01]
DOI:
10.1172/JCI123106
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