VEGFR2 regulates endothelial differentiation of colon cancer cells

Abstract

BackgroundRecent studies suggested that cancer stem-like cells contribute to tumor vasculogenesis by differentiating into endothelial cells. However, such process is governed by still undefined mechanism.MethodsAt varying differentiation levels, three representative colon cancer cells were cultured in endothelial-inducing conditioned medium: human colon cancer cells HCT116 (HCT116) (poorly differentiated), SW480 (moderately differentiated), and HT29 (well differentiated). We tested for expression of endothelial markers (cluster of differentiation (CD) 31, CD34, and vascular endothelial (VE)-cadherin and their ability to form tube-like structures in 3D culture. We also observed VEGF secretion and expressions of endothelial markers and VEGFRs in HCT116 cells under hypoxia to simulate physiological conditions. In in vitro and in xenotransplantation experiments, VE growth factor receptor 2 (VEGFR2) antagonist SKLB1002 was used to test effect of VEGFR2 in endothelial differentiation of HCT116 cells. Expression levels of VEGFR2 and VE-cadherin were assessed by immunohistochemistry of human colon cancer tissues to evaluate clinicopathological significance of VEGFR2.ResultsAfter culturing in endothelial-inducing conditioned medium, poorly differentiated HCT116 cells expressed endothelial markers and formed tube-like structure in vitro. HCT116 cells secreted more endogenous VEGF and expressed higher VEGFR2 under hypoxia. SKLB1002 impaired endothelial differentiation in vitro and xenotransplantation experiments, suggesting a VEGFR2-dependent mechanism. Increased expression of VEGFR2 correlated with differentiation, metastasis/recurrence, and poor prognosis in 203 human colon cancer samples. Positive correlation was observed between VEGFR2 and VE-cadherin expression.ConclusionsVEGFR2 regulates endothelial differentiation of colon cancer cell and may be potential platform for anti-angiogenesis cancer therapy.

Role of VEGF-A and LRG1 in Abnormal Angiogenesis Associated With Diabetic Nephropathy

“…VEGFR2 is the main mediator in promoting mitogenic, angiogenic, and vascular permeability effects ( Ferrara et al, 2003 ; Shibuya, 2006 ) ( Figure 1 ). The VEGF-A binding sites are initially located on the vascular ECs cell surface, the sites where VEGFR2 is expressed ( Ferrara et al, 2003 ; Liu Z. Y. et al, 2017 ). The binding between VEGF-A and VEGFR2 undergoes dimerization and tyrosine phosphorylation and then activates the downstream signaling pathways in relation to angiogenesis in ECs and some cellular responses such as mitogenic and survival signal as well ( Abhinand et al, 2016 ).…”

A Network Pharmacology Approach to Uncover the Molecular Mechanisms of Herbal Formula Ban‐Xia‐Xie‐Xin‐Tang

“…In M46, protein FLT3, RASA1, and PTPRJ are considered as key signaling nodes to coordinately regulate various cellular processes including cellular proliferation, differentiation, mitotic cycle, and oncogenic transformation [ 88 – 95 ]. KDR acts as a major growth factor for endothelial cells, allowing regulation of endothelial proliferation, migration, and survival[ 96 ], which is associated with a variety of tumor types [ 97 , 98 ].…”

Design, Synthesis and Biological Activity Evaluation of S-Substituted 1H-5-Mercapto-1,2,4-Triazole Derivatives as Antiproliferative Agents in Colorectal Cancer

“…According to the molecular docking study, this compound obtained a very good score against VEGFR2, the main proangiogenic factor in various types of cancer (Araújo et al, 2015 ). In colon cancer, VEGFR2 regulates endothelial differentiation and its expression correlates with metastasis or tumor recurrence followed by poor prognosis (Liu et al, 2017 ). The activity results may therefore be attributed to VEGFR2 inhibition as the molecular docking indicates.…”

“…Vascular endothelial growth factor receptor 2 (VEGFR2) is a type V receptor tyrosine kinase encoded by the KDR gene (Miettinen et al, 2012 ), known to be expressed mostly in endothelial cells (Liu et al, 2017 ). This receptor after being activated, by responding to VEGF-A signal, triggers a phosphorylation cascade, promoting regulation of nuclear targets and increased endothelial proliferation and migration (Miettinen et al, 2012 ).…”