Aspirin suppresses tumor cell-induced angiogenesis and their incongruity
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Tumor neovascularization/tumor angiogenesis is a pathophysiological process in which new blood vessels are formed from existing blood vessels in the primary tumors to supply adequate oxygen and nutrition to cancer cells for their proliferation and metastatic growth to the distant organs. Therefore, controlling tumor angiogenesis is an attractive target for cancer therapy. Structural abnormalities of the vasculature (i.e., leakiness due to the abnormal lining of pericytes on the microvessels) are one of the critical features of tumor angiogenesis that sensitizes vascular cells to cytokines and helps circulating tumor cells to metastasize to distant organs. Our goal is to repurpose the drugs that may prevent tumor angiogenesis or normalize the vessels by repairing leakiness via recruiting pericytes or both. In this study, we tested whether aspirin (ASA), which could block primary tumor growth, regulates tumor angiogenesis. We investigated the effects of low (1 mM) and high (2.5 mM) doses of ASA (direct effect), and ASA-treated or untreated triple negative breast cancer (TNBC) cells’ conditioned media (indirect effect) on endothelial cell physiology. These include in vitro migration using modified Boyden chamber assay, in vitro capillary-like structure formation on Matrigel, interactions of pericytes-endothelial cells and cell permeability using in vitro endothelial permeability assay. We also examined the effect of ASA on various molecular factors associated with tumor angiogenesis. Finally, we found the outcome of ASA treatment on in vivo tumor angiogenesis. We found that ASA-treatment (direct or indirect) significantly blocks in vitro migration and capillary-like structure formation by endothelial cells. Besides, we found that ASA recruits pericytes from multipotent stem cells and helps in binding with endothelial cells, which is a hallmark of normalization of blood vessels, and decreases in vitro permeability through endothelial cell layer. The antiangiogenic effect of ASA was also documented in vivo assays. Mechanistically, ASA treatment blocks several angiogenic factors that are associated with tumor angiogenesis, and suggesting ASA blocks paracrine-autocrine signaling network between tumor cells and endothelial cells. Collectively, these studies implicate aspirin with proper dose may provide potential therapeutic for breast cancer via blocking as well as normalizing tumor angiogenesis.
KeywordsBreast cancer Aspirin Hyperpermeability Metastasis Leaky blood vessels
Vascular Endothelial Growth Factor
Human Umbilical Vein Endothelial Cell
We thank the members of Kansas City VA Research Office and Midwest Biomedical Research Foundation Administrative and clerical supports.
Conception and design: S. K. Banerjee, S. Banerjee I. Haque and G. Maity; Development of Methodology: G. Maity and A. Ghosh, I. Haque and S. Banerjee; Acquisition of Data: G. Maity and J. Chakraborty; Analysis and Interpretation of Data: G. Maity, A. Ghosh, J. Chakraborty, S. Banerjee and S.K. Banerjee; Writing and review of the manuscript: G. Maity, J. Chakraborty, S. Banerjee and S. K. Banerjee; Administrative, technical or material support: G. Maity, A. Ghosh and S. K. Banerjee, and Study supervision: S. K. Banerjee.
The work is supported by Merit review grant from Department of Veterans Affairs (Sushanta K. Banerjee, 5I01BX001989–04 and Snigdha Banerjee, I01BX001002–05), KUMC Lied Basic Science Grant Program (SKB), and Grace Hortense Greenley Trust, directed by The Research Foundation in memory of Eva Lee Caldwell (SKB).
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All the authors of this manuscript have agreed to publish this article.
No potential conflicts of interest were disclosed.
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