![]() ![]() It is composed of collagens, proteoglycans (PGs), glycosaminoglycans (GAGs), elastin, laminins, and fibronectins ( Theocharis et al., 2016). The ECM plays an important role in cell adhesion, migration, intercellular communication, and differentiation ( Provenzano et al., 2009). This is especially significant because the degree of susceptibility of ECs to selective interactions depends on their organ/tissue specificity on the one hand and biological commitment to the concerned disease on the other.Ī major component of the microenvironment is the extracellular matrix (ECM), which is a set of extracellular molecules that provide structural and biochemical support for cells. This process prompts cancer propagation and metastasis thus, it is crucial to understand the crosstalk between endothelial cells and their microenvironment and how it is different in biologically healthy and pathological tissues. ![]() ECs gain a few mesenchymal cell features such as loss of tight junctions, increased motility, and increased level of extracellular matrix proteins such as collagens, elastin, fibronectins, and laminins ( Kim, 2018). In this process, endothelial cells (ECs) present a reduced expression of typical endothelial markers, which include vascular endothelial cadherin (VE-cadherin), platelet endothelial cell adhesion molecule (PECAM-1/CD31), and von Willebrand Factor (vWF) ( Kim, 2018). Aside from angiogenesis, hypoxia influences ECs proliferation, migration, and deep phenotypic changes up to the induction of endothelial to mesenchymal transition (EndMT) in the microenvironment of hypoxia-dependent pathologies ( Carreau et al., 2011). These cells are the key players in pathological angiogenesis driven by hypoxia, defined as lower than physiological oxygen tension. ![]() The tumor microenvironment contributes not only to the diversity of tumor blood vessels in tissues but also to endothelial cell heterogeneity. Moreover, it indicates the role of miR-200b-3p, that is, regulating EndMT in pathological ECs and silencing several angiogenic growth factors and their receptors by directly targeting their mRNA transcripts. The gene expression profile confirms the EndMT phenotype of tumor-derived ECs and migratory properties acquisition. Moreover, the analysis of the 10 most intensively modified miRNAs, when breast tumor–derived ECs were compared to healthy ECs, shed light on miR-200b-3p, which is strongly upregulated in HBCa.MECs when compared to HBH.MECs.ĭiscussion and conclusion: The pathological ECs differed significantly, both phenotypically and functionally, from the normal corresponding tissue, thus influencing their microenvironment cross-talk. NGS also identified collagens, laminins, fibronectins, and integrins, as being deregulated in tumor-derived ECs. The deregulated genes, validated by qPCR, included SPP1, ITGB6, COL4A4, ADAMST2, LAMA1, GAS6, PECAM1, ELN, FBLN2, COL6A3, and COL9A3. NGS data identified this process to be altered in cancer ECs through extracellular matrix (ECM) organization. In hypoxia, healthy ECs migrate slower than they do in normoxia, as opposed to HBCa.MEC, where no decreased migration ability is induced by hypoxia due to EndMT features. Results: Hypoxia influences EC migration properties in wound healing assays. Mimic miR-200b-3p was used in HBH.MEC, and the targets VEGF, Bcl2, ROCK2, and SP1 were checked. The validation of NGS data from RNA and miRNA was estimated by qPCRs. Global gene expression analysis with NGS was carried out to detect new pathways altered in pathological ECs and find the most changed miRNAs. By using the wound healing test, we investigated the migration abilities of ECs. The experiments were performed in normoxia and hypoxia for 48 h. Methodology: Immortalized lines of ECs from the same patient with breast cancer, healthy breast tissue (HBH.MEC), and primary tumor (HBCa.MEC) were used. This study aimed to evidence the influences of the tumor microenvironment on the global gene expression pattern characteristic for ECs and the distinct responses displayed by tumor-derived ECs in comparison to the healthy endothelium during endothelial to mesenchymal transition (EndMT) and its regulation by miR-200-b-3p. Introduction: Hypoxia shapes the tumor microenvironment, modulates distinct cell population activities, and activates pathological angiogenesis in cancer, where endothelial cells (ECs) are the most important players.
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