title: Tie2/TEK modulates the interaction of glioma and brain tumor stem cells with endothelial cells and promotes an invasive phenotype.
abstract: Malignant gliomas are the prototype of highly infiltrative tumors and this characteristic is the main factor for the inevitable tumor recurrence and short survival after most aggressive therapies. The aberrant communication between glioma cells and tumor microenvironment represents one of the major factors regulating brain tumor dispersal. Our group has previously reported that the tyrosine kinase receptor Tie2/TEK is expressed in glioma cells and brain tumor stem cells and is associated with the malignant progression of these tumors. In this study, we sought to determine whether the angiopoietin 1 (Ang1)/Tie2 axis regulates crosstalk between glioma cells and endothelial cells. We found that Ang1 enhanced the adhesion of Tie2-expressing glioma and brain tumor stem cells to endothelial cells. Conversely, specific small interfering RNA (siRNA) knockdown of Tie2 expression inhibited the adhesion capability of glioma cells. Tie2 activation induced integrin β1 and N-cadherin upregulation, and neutralizing antibodies against these molecules inhibited the adhesion of Tie2-positive glioma cells to endothelial cells. In 2D and 3D cultures, we observed that Ang1/Tie2 axis activation was related to increased glioma cell invasion, which was inhibited by using Tie2 siRNA. Importantly, intracranial co-implantation of Tie2-positive glioma cells and endothelial cells in a mouse model resulted in diffusely invasive tumors with cell clusters surrounding glomeruloid vessels mimicking a tumoral niche distribution. Collectively, our results provide new information about the Tie2 signaling in glioma cells that regulates the cross-talk between glioma cells and tumor microenvironment, envisioning Tie2 as a multi-compartmental target for glioma therapy.
authors.affiliation: Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Martin
authors.affiliation: Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Fueyo
authors.affiliation: Severance Hospital Integrative Research Institute for Cerebral and Cardiovascular Disease, Yonsei University Health System, Seoul, Korea.
authors.forename: Ok-Hee
authors.initials: OH
authors.lastname: Lee
authors.affiliation: Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Nahir
authors.initials: N
authors.lastname: Cortes-Santiago
authors.affiliation: Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Marta M
authors.initials: MM
authors.lastname: Alonso
authors.affiliation: Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Aldape
authors.affiliation: Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Colman
authors.affiliation: Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.|Department of Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
authors.forename: Candelaria
authors.initials: C
authors.lastname: Gomez-Manzano
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D002448:Cell Adhesion; D002450:Cell Communication / Q000235:genetics; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D010641:Phenotype; D034741:RNA, Small Interfering / Q000494:pharmacology; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics / Q000502:physiology
chemical_list: D034741:RNA, Small Interfering; D042787:Receptor, TIE-2