High baseline Tie1 level predicts poor survival in metastatic breast cancer

Abstract

Background Angiopoietin growth factors (Angs) regulate angiogenesis and lymphangiogenesis by binding to the endothelial Tie2 receptor. Ang2 expression is elevated in tissue hypoxia and inflammation, which also induce cleavage of the extracellular domain of the orphan Tie1 receptor. Here we have examined if the concentrations of Ang2 and the soluble extracellular domain of Tie1 in patient plasma are associated with the prognosis of patients with metastatic breast cancer. Methods Plasma Tie1 and Ang2 levels were measured in metastatic breast cancer patients treated in a phase II trial with a taxane-bevacizumab combination chemotherapy in the first-line treatment setting. They were analyzed before treatment, after 6 weeks and 6 months of treatment, and at the final study visit. Using the median concentrations as cutoffs, Tie1 and Ang2 data were dichotomized into low and high concentration groups. Additionally, we analyzed Tie1 concentrations in plasma from 10 healthy women participating in a breast cancer primary prevention study. Results Plasma samples were available from 58 (89%) of the 65 patients treated in the trial. The baseline Tie1 levels of the healthy controls were significantly lower than those of the metastatic patients ( p < 0.001). The overall survival of the patients with a high baseline Tie1 level was significantly shorter (multivariate HR 3.07, 95% CI 1.39–6.79, p = 0.005). Additionally, the progression-free survival was shorter for patients with a high baseline Tie1 level (multivariate HR 3.78, 95% CI 1.57–9.09, p = 0.003). In contrast, the baseline Ang2 levels had no prognostic impact in a multivariate Cox proportional hazard regression analysis. The combined analysis of baseline Tie1 and Ang2 levels revealed that patients with both high Tie1 and high Ang2 baseline levels had a significantly shorter overall survival than the patients with low baseline levels of both markers (multivariate HR for overall survival 4.32, 95% CI 1.44–12.94, p = 0.009). Conclusions This is the first study to demonstrate the prognostic value of baseline Tie1 plasma concentration in patients with metastatic breast cancer. Combined with the results of the Ang2 analyses, the patients with both high Tie1 and Ang2 levels before treatment had the poorest survival. Trial registration Clinicaltrials.gov : NCT00979641, registration date 19-DEC-2008. The regional Ethics Committee: R08142M, registration date 18-NOV-2008.

Superparamagnetic iron oxide nanoparticles drive miR-485-5p inhibition in glioma stem cells by silencing Tie1 expression

“…This study was the first to demonstrate the function of Tie1 in gliomas. Tie1 is often studied in the occurrence of vascular development and cardiovascular diseases [10][11][12][13][14][15][16][17], At present, there are no reports on its relationship with glioma, particularly glioma stem cell viability. However, we employed bioinformatics software for predicting protein-protein interactions and found that Tie1 can interact with some cellular factors, particularly nerve growth factors such as BDNF, GDNF, and GFAP.…”

“…Studies have shown that Tie1 is associated with angiogenesis, vascular maturation, tissue remodelling, and inflammation. Recent studies have also shown that elevated Tie1 expression is intimately associated with atherosclerosis and the stemness of cancer stem cells [12,[14][15][16][17]. However, there have beenno reports so far on the relationship between Tie1 and HuGSCs.…”

Soluble Compounds Released by Hypoxic Stroma Confer Invasive Properties to Pancreatic Ductal Adenocarcinoma

“…These proteins are crucial for the remodeling and maturation of tumor vasculature [67]. TIE1 is believed to form a complex with angiopoietins and sustain TIE2 signaling in contacting cells [68,69] and was found increased in several malignancies [70][71][72]. The exact functions of TIE1 in cancer remain unknown, but given the contributions of TIE1 and -2 to angiogenesis, their role in hypoxic tissue seems especially relevant.…”

Hypoxia-induced Tie1 Drives Stemness and Cisplatin Resistance in Non-small Cell Lung Carcinoma Cells

“…In NSCLC, a female group of patients with adenocarcinoma and high expression of Tie1 had lower overall survival than those with a low expression of Tie1 [13]. In a recent phase II trial with taxane-bevacizumab combination chemotherapy, elevated levels of ANG2 and Tie1 in the blood plasma of patients with metastatic breast cancer were associated with shorter overall survival than baseline levels [14]. During hypoxia and in ammation, Tie1 was found to induce the antagonistic disruptive form of ANG2 [15,16].…”