Solid tumors cannot grow beyond a few millimeters in size without the support of co-opted stromal cells. The function of different stromal cells in the tumor microenvironment may be subverted in ways that are beneficial for tumor progression. Examples are the tumor-induced and specific polarization of immune/inflammatory cells, conversion of fibroblasts into tumor-supportive myofibroblasts, and dysfunctional tumor endothelial cells. Irregular and hyper-permeable vasculature occurs early when only a few hundred-tumor cells are present. Leaky tumor blood vessels deposit fibrin in a perivascular niche that forms scaffolds for tumor cell growth and invasion as well as sparks angiogenesis. Using a miRNA screen of freshly isolated TECs, I identified a TGF?-regulated miRNA (miR-30c) that controls vascular-directed fibrinolysis in tumors. miR-30c is increased in TECs relative to normal endothelial cells (NECs) whereas its target PAI-1 (a fibrinolysis inhibitor) is strikingly decreased. TECs secrete less PAI-1 and they rapidly degrade fibrin scaffolds resulting in aberrant in vitro sprouting. However, TGF? and miR-30c antagomiRs reduce miR-30c expression which re-instates PAI-1 secretion, diminishes fibrinolysis, and ?normalizes? TEC sprouting in vitro. miR-30c antagomiRs coupled to vascular-tropic nanoparticles enforce vascular-specific PAI-1 expression and strikingly promote robust orthotopic mammary tumor growth in vivo. Thus, manipulation of vascular-specific expression of miR-30c in tumors promotes tumor growth likely due to enhanced fibrin-mediated angiogenesis. I propose an axis between TGF?, miR-30c and PAI-1 in TECs controls the rate of perivascular fibrinolysis and is therefore an important effector of tumor angiogenesis and progression.

Public Health Relevance

Tumor associated vasculature displays morphological and functional irregularities leading to vessel leakiness and deposition of perivascular fibrin. Fibrin that escapes leaky tumor vessels acts as a scaffold for tumor cell invasion and is a catalyst for angiogenesis. The experiments outlined in this project will explore the role of a TGF?-regulated miRNA during vascular-directed fibrinolysis and tumor angiogenesis. By delineating this pathway, my long-term goals are to explore and clarify the relationship between vascular-mediated fibrinolysis, angiogenesis, and tumor growth in vivo.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31CA213793-04
Application #
9649204
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Schmidt, Michael K
Project Start
2017-04-01
Project End
2020-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Virginia
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904