Abstract
Tumor microenvironments shape aggressiveness and are largely maintained by the conditions of angiogenesis formation. Thus, endothelial cells’ (ECs) biological reactions are crucial to understand and control the design of efficient therapies. In this work, we used models of ECs to represent a breast cancer tumor site as well as the same, healthy tissue. Cells characterization was performed at the transcriptome and protein expression levels, and the cells functional biological responses (angiogenesis and permeability) were assessed. We showed that the expression of proteins specific to ECs (ACE+, VWF+), their differentiation (CD31+, CD 133+, CD105+, CD34-), their adhesion properties (ICAM-1+, VCAM-1+, CD62-L+), and their barrier formation (ZO-1+) were all downregulated in tumor-derived ECs. NGS-based differential transcriptome analysis confirmed CD31-lowered expression and pointed to the increase of Ephrin-B2 and SNCAIP, indicative of dedifferentiation. Functional assays confirmed these differences; angiogenesis was impaired while permeability increased in tumor-derived ECs, as further validated by the distinctly enhanced VEGF production in response to hypoxia, reflecting the tumor conditions. This work showed that endothelial cells differed highly significantly, both phenotypically and functionally, in the tumor site as compared to the normal corresponding tissue, thus influencing the tumor microenvironment.
Highlights
As breast cancer is one of the major causes of death among the female population worldwide, numerous studies are carried on breast tumor angiogenesis [1]
Cells were stained for endothelial cell-specific markers (CD31, von Willebrand factor (VWF), ACE, CD133, CD34, CD105) and related to pathological states of tissue (PDPN, AP, αSMA, EGFR)
PECAM-1 was identified in NGS as being downregulated in breast tumor endothelial cells (TECs) vs. breast normal endothelial cells (NECs), which underlines the fact that the tumor microenvironment alters the endothelial cells (ECs) phenotype
Summary
As breast cancer is one of the major causes of death among the female population worldwide, numerous studies are carried on breast tumor angiogenesis [1]. In the great majority of them, human umbilical vein endothelial cells (HUVECs) were used as the universal model of endothelial cells (ECs). Such a widespread use may lead to skewed observations due to the heterogeneity of donors and changes in phenotype caused by long-term culture [2]. They do not represent, by any means, the organs in which cancers originate. Setting up a relevant experimental models for angiogenesis is crucial to better understanding the molecular mechanisms triggered during tumor growth and metastasis and to provide diagnostic, prognostic and treatment opportunities
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