Showing papers on "TIE1 published in 2018"

Endothelial Tie1–mediated angiogenesis and vascular abnormalization promote tumor progression and metastasis

Abstract: The endothelial tyrosine kinase receptor Tie1 remains poorly characterized, largely owing to its orphan receptor status. Global Tie1 inactivation causes late embryonic lethality, thereby reflecting its importance during development. Tie1 also plays pivotal roles during pathologies such as atherosclerosis and tumorigenesis. In order to study the contribution of Tie1 to tumor progression and metastasis, we conditionally deleted Tie1 in endothelial cells at different stages of tumor growth and metastatic dissemination. Tie1 deletion during primary tumor growth in mice led to a decrease in microvessel density and an increase in mural cell coverage with improved vessel perfusion. Reduced angiogenesis and enhanced vascular normalization resulted in a progressive increase of intratumoral necrosis that caused a growth delay only at later stages of tumor progression. Concomitantly, surgical removal of the primary tumor decreased the number of circulating tumor cells, reduced metastasis, and prolonged overall survival. Additionally, Tie1 deletion in experimental murine metastasis models prevented extravasation of tumor cells into the lungs and reduced metastatic foci. Taken together, the data support Tie1 as a therapeutic target by defining its regulatory functions during angiogenesis and vascular abnormalization and identifying its role during metastasis.

IGF2 and IGF1R identified as novel tip cell genes in primary microvascular endothelial cell monolayers

Abstract: Tip cells, the leading cells of angiogenic sprouts, were identified in cultures of human umbilical vein endothelial cells (HUVECs) by using CD34 as a marker. Here, we show that tip cells are also present in primary human microvascular endothelial cells (hMVECs), a more relevant endothelial cell type for angiogenesis. By means of flow cytometry, immunocytochemistry, and qPCR, it is shown that endothelial cell cultures contain a dynamic population of CD34+ cells with many hallmarks of tip cells, including filopodia-like extensions, elevated mRNA levels of known tip cell genes, and responsiveness to stimulation with VEGF and inhibition by DLL4. Furthermore, we demonstrate that our in vitro tip cell model can be exploited to investigate cellular and molecular mechanisms in tip cells and to discover novel targets for anti-angiogenesis therapy in patients. Small interfering RNA (siRNA) was used to knockdown gene expression of the known tip cell genes angiopoietin 2 (ANGPT2) and tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE1), which resulted in similar effects on tip cells and sprouting as compared to inhibition of tip cells in vivo. Finally, we identified two novel tip cell-specific genes in CD34+ tip cells in vitro: insulin-like growth factor 2 (IGF2) and IGF-1-receptor (IGF1R). Knockdown of these genes resulted in a significant decrease in the fraction of tip cells and in the extent of sprouting in vitro and in vivo. In conclusion, this study shows that by using our in vitro tip cell model, two novel essential tip cells genes are identified.

Temporal and Spatial Post-Transcriptional Regulation of Zebrafish tie1 mRNA by Long Noncoding RNA During Brain Vascular Assembly.

Abstract: Objective— Tie1 (tyrosine kinase containing immunoglobulin and epidermal growth factor homology 1), an endothelial and hematopoietic cell–specific receptor tyrosine kinase, is an important regulato...

Anti-angiogenic Targets: Angiopoietin and Angiopoietin-Receptors

Abstract: Tumor blood vessel formation (angiogenesis) is essential for tumor growth and metastasis. Two main endothelial ligand–receptor pathways regulating angiogenesis are vascular endothelial growth factor (VEGF) receptor and angiopoietin-TIE receptor pathways. The angiopoietin-TIE pathway is required for the remodeling and maturation of the blood and lymphatic vessels during embryonic development after VEGF and VEGF-C mediated development of the primary vascular plexus. Angiopoietin-1 (ANGPT1) stabilizes the vasculature after angiogenic processes, via tyrosine kinase with immunoglobulin-like and EGF-like domains 2 (TIE2) activation. In contrast, ANGPT2 is upregulated at sites of vascular remodeling. ANGPT2 is secreted by activated endothelial cells in inflammation, promoting vascular destabilization. ANGPT2 has been found to be expressed in many human cancers. Intriguingly, in preclinical models inhibition of ANGPT2 has provided promising results in preventing tumor angiogenesis, tumor growth, and metastasis, making it an attractive candidate to target in tumors. However, until now the first ANGPT2 targeting therapies have been less effective in clinical trials than in experimental models. Additionally, in preclinical models combined therapy against ANGPT2 and VEGF or immune checkpoint inhibitors has been superior to monotherapies, and these pathways are also targeted in early clinical trials. In order to improve current anti-angiogenic therapies and successfully exploit ANGPT2 as a target for cancer treatment, the biology of the angiopoietin-TIE pathway needs to be profoundly clarified.