title: RAGE expression in tumor-associated macrophages promotes angiogenesis in glioma.
abstract: Interaction of RAGE (the receptor for advanced glycation endproducts) with its ligands can promote tumor progression, invasion, and angiogenesis. Although blocking RAGE signaling has been proposed as a potential anticancer strategy, functional contributions of RAGE expression in the tumor microenvironment (TME) have not been investigated in detail. Here, we evaluated the effect of genetic depletion of RAGE in TME on the growth of gliomas. In both invasive and noninvasive glioma models, animal survival was prolonged in RAGE knockout (Ager(-/-)) mice. However, the improvement in survival in Ager(-/-) mice was not due to changes in tumor growth rate but rather to a reduction in tumor-associated inflammation. Furthermore, RAGE ablation in the TME abrogated angiogenesis by downregulating the expression of proangiogenic factors, which prevented normal vessel formation, thereby generating a leaky vasculature. These alterations were most prominent in noninvasive gliomas, in which the expression of VEGF and proinflammatory cytokines were also lower in tumor-associated macrophages (TAM) in Ager(-/-) mice. Interestingly, reconstitution of Ager(-/-) TAM with wild-type microglia or macrophages normalized tumor vascularity. Our results establish that RAGE signaling in glioma-associated microglia and TAM drives angiogenesis, underscoring the complex role of RAGE and its ligands in gliomagenesis.
authors.affiliation: Department of General Surgery, China Japan Union Hospital of Jilin University, Changchun, Jilin Province, P.R.China.
authors.forename: Xuebo
authors.initials: X
authors.lastname: Chen
authors.affiliation: Division of Neurosurgery, City of Hope Beckman Research Institute.
authors.forename: Leying
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Neurosurgery, City of Hope Beckman Research Institute.
authors.forename: Ian Y
authors.initials: IY
authors.lastname: Zhang
authors.affiliation: Research Center of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zhejiang University, Hangzhou, P.R. China.
authors.forename: Junling
authors.initials: J
authors.lastname: Liang
authors.affiliation: Department of Emergency Surgery, Qilu Hospital of Shandong University, Jinan, Shandong Province, P.R. China.
authors.forename: Huaqing
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Third Xiangya Hospital, Central South University, Changsha Hunan, P.R. China.
authors.forename: Mao
authors.initials: M
authors.lastname: Ouyang
authors.affiliation: Research Center of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zhejiang University, Hangzhou, P.R. China.
authors.forename: Shihua
authors.initials: S
authors.lastname: Wu
authors.affiliation: Laboratório de Morfogênese Celular, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil, Bolsista do CNPq.
authors.forename: Anna Carolina Carvalho
authors.initials: ACC
authors.lastname: da Fonseca
authors.affiliation: Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Beckman Research Institute.
authors.forename: Lihong
authors.initials: L
authors.lastname: Weng
authors.affiliation: Department of Biochemistry and Molecular Vascular Biology, Kanazawa University, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Biochemistry and Molecular Vascular Biology, Kanazawa University, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Division of Molecular Diabetes Research, City of Hope Beckman Research Institute.
authors.forename: Rama
authors.initials: R
authors.lastname: Natarajan
authors.affiliation: Division of Neurosurgery, City of Hope Beckman Research Institute.|Department of Cancer Immunotherapeutics & Tumor Immunology, City of Hope Beckman Research Institute.
authors.forename: Behnam
authors.initials: B
authors.lastname: Badie
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D059016:Tumor Microenvironment / Q000235:genetics*
chemical_list: D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic