title: Tumoral RANKL activates astrocytes that promote glioma cell invasion through cytokine signaling.
abstract: The invasiveness of glioblastoma is a major cause of poor prognosis and relapse. However, the molecular mechanism controlling glioma cell invasion is poorly understood. Here, we report that receptor activator of nuclear factor kappa-B (NFκB) ligand (RANKL) promotes glioma cell invasion in vivo, but not in vitro. Unlike the invasiveness under in vitro culture conditions, in vivo xenograft studies revealed that LN229 cells expressing high endogenous RANKL generated more invasive tumors than U87MG cells expressing relatively low endogenous RANKL. Consistently, RANKL-overexpressing U87MG resulted in invasive tumors, whereas RANKL-depleted LN229 generated rarely invasive tumors. We found that the number of activated astrocytes was markedly increased in the periphery of RANKL-high invasive tumors. RANKL activated astrocytes through NFκB signaling and these astrocytes in turn secreted various factors which regulate glioma cell invasion. Among them, transforming growth factor β (TGF-β) signaling was markedly increased in glioblastoma specimens and xenograft tumors expressing high levels of RANKL. These results indicate that RANKL contributes to glioma invasion by modulating the peripheral microenvironment of the tumor, and that targeting RANKL signaling has important implications for the prevention of highly invasive glioblastoma.
authors: School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea; Institute of Life Science and Natural Resources, Korea University, Seoul 136-713, Republic of Korea.
authors: Jun-Kyum
authors: JK
authors: Kim
authors: School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea; Institute of Life Science and Natural Resources, Korea University, Seoul 136-713, Republic of Korea.
authors: Xiong
authors: X
authors: Jin
authors: School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea.
authors: Young-Woo
authors: YW
authors: Sohn
authors: Institute of Life Science and Natural Resources, Korea University, Seoul 136-713, Republic of Korea.
authors: Xun
authors: X
authors: Jin
authors: School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea; Institute of Life Science and Natural Resources, Korea University, Seoul 136-713, Republic of Korea.
authors: Hee-Young
authors: HY
authors: Jeon
authors: School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea; Institute of Life Science and Natural Resources, Korea University, Seoul 136-713, Republic of Korea.
authors: Eun-Jung
authors: EJ
authors: Kim
authors: School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea.
authors: Seok Won
authors: SW
authors: Ham
authors: School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea; Institute of Life Science and Natural Resources, Korea University, Seoul 136-713, Republic of Korea.
authors: Hye-Min
authors: HM
authors: Jeon
authors: School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea.
authors: So-Young
authors: SY
authors: Chang
authors: Institute of Life Science and Natural Resources, Korea University, Seoul 136-713, Republic of Korea.
authors: Se-Yeong
authors: SY
authors: Oh
authors: Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang 410-769, Republic of Korea.
authors: Jinlong
authors: J
authors: Yin
authors: School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea; Department of Neurological Surgery, The Ohio State University, Columbus, OH 43210, USA.
authors: Sung-Hak
authors: SH
authors: Kim
authors: Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang 410-769, Republic of Korea.
authors: Jong Bae
authors: JB
authors: Park
authors: Department of Neurological Surgery, The Ohio State University, Columbus, OH 43210, USA; James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors: Ichiro
authors: I
authors: Nakano
authors: School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea. Electronic address: hg-kim@korea.ac.kr.
authors: Hyunggee
authors: H
authors: Kim
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000502:physiology*; D001932:Brain Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D016207:Cytokines / Q000502:physiology*; D005909:Glioblastoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D053245:RANK Ligand / Q000502:physiology*; D015398:Signal Transduction; D059016:Tumor Microenvironment
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D053245:RANK Ligand; C505688:TNFSF11 protein, human
keywords: Astrocyte; Glioblastoma; RANKL signaling; Tumor-invasive microenvironment