title: NG2 proteoglycan-dependent recruitment of tumor macrophages promotes pericyte-endothelial cell interactions required for brain tumor vascularization.
abstract: Early stage growth of intracranial B16F10 tumors is reduced by 87% in myeloid-specific NG2 null (Mac-NG2ko) mice and by 77% in pericyte-specific NG2 null (PC-NG2ko) mice, demonstrating the importance of the NG2 proteoglycan in each of these stromal compartments. In both genotypes, loss of pericyte-endothelial cell interaction results in numerous structural defects in tumor blood vessels, including decreased formation of endothelial cell junctions and decreased assembly of the vascular basal lamina. All vascular deficits are larger in Mac-NG2ko mice than in PC-NG2ko mice, correlating with the greater decrease in pericyte-endothelial cell interaction in Mac-NG2ko animals. Accordingly, tumor vessels in Mac-NG2ko mice have a smaller diameter, lower degree of patency, and higher degree of leakiness than tumor vessels in PC-NG2ko mice, leading to less efficient tumor blood flow and to increased intratumoral hypoxia. While reduced pericyte interaction with endothelial cells in PC-NG2ko mice is caused by loss of NG2-dependent pericyte activation of β1 integrin signaling in endothelial cells, reduced pericyte-endothelial cell interaction in Mac-NG2ko mice is due to a 90% reduction in NG2-dependent macrophage recruitment to tumors. The absence of a macrophage-derived signal(s) in Mac-NG2ko mice results in the loss of pericyte ability to associate with endothelial cells, possibly due to reduced expression of N-cadherin by both pericytes and endothelial cells.
authors.affiliation: Sanford-Burnham Medical Research Institute; Cancer Center ; La Jolla, CA USA ; Department of Biochemistry; Faculty of Medicine ; Fukuoka University , Fukuoka, Japan.
authors.forename: Fusanori
authors.initials: F
authors.lastname: Yotsumoto
authors.affiliation: Sanford-Burnham Medical Research Institute; Cancer Center ; La Jolla, CA USA ; Biologics Business; Research and Development Center ; Hanwha Chemical ; Daejeon, South Korea.
authors.forename: Weon-Kyoo
authors.initials: WK
authors.lastname: You
authors.affiliation: Sanford-Burnham Medical Research Institute; Cancer Center ; La Jolla, CA USA.
authors.forename: Pilar
authors.initials: P
authors.lastname: Cejudo-Martin
authors.affiliation: Sanford-Burnham Medical Research Institute; Cancer Center ; La Jolla, CA USA.
authors.forename: Karolina
authors.initials: K
authors.lastname: Kucharova
authors.affiliation: Department of Cellular Neurobiology; Brain Research Institute ; Niigata University , Niigata, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakimura
authors.affiliation: Sanford-Burnham Medical Research Institute; Cancer Center ; La Jolla, CA USA.
authors.forename: William B
authors.initials: WB
authors.lastname: Stallcup
keywords: NG2 proteoglycan; macrophage recruitment; pericyte-endothelial cell interaction; tumor microenvironment; tumor vascularization