PMID- 25079688 OWN - NLM STAT- MEDLINE DCOM- 20141111 LR - 20201219 IS - 1872-7980 (Electronic) IS - 0304-3835 (Linking) VI - 353 IP - 2 DP - 2014 Oct 28 TI - Tumoral RANKL activates astrocytes that promote glioma cell invasion through cytokine signaling. PG - 194-200 LID - S0304-3835(14)00399-1 [pii] LID - 10.1016/j.canlet.2014.07.034 [doi] AB - 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 (NFkappaB) 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 NFkappaB signaling and these astrocytes in turn secreted various factors which regulate glioma cell invasion. Among them, transforming growth factor beta (TGF-beta) 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. CI - Copyright (c) 2014 Elsevier Ireland Ltd. All rights reserved. FAU - Kim, Jun-Kyum AU - Kim JK AD - 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. FAU - Jin, Xiong AU - Jin X AD - 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. FAU - Sohn, Young-Woo AU - Sohn YW AD - School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea. FAU - Jin, Xun AU - Jin X AD - Institute of Life Science and Natural Resources, Korea University, Seoul 136-713, Republic of Korea. FAU - Jeon, Hee-Young AU - Jeon HY AD - 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. FAU - Kim, Eun-Jung AU - Kim EJ AD - 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. FAU - Ham, Seok Won AU - Ham SW AD - School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea. FAU - Jeon, Hye-Min AU - Jeon HM AD - 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. FAU - Chang, So-Young AU - Chang SY AD - School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea. FAU - Oh, Se-Yeong AU - Oh SY AD - Institute of Life Science and Natural Resources, Korea University, Seoul 136-713, Republic of Korea. FAU - Yin, Jinlong AU - Yin J AD - Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang 410-769, Republic of Korea. FAU - Kim, Sung-Hak AU - Kim SH AD - 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. FAU - Park, Jong Bae AU - Park JB AD - Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang 410-769, Republic of Korea. FAU - Nakano, Ichiro AU - Nakano I AD - Department of Neurological Surgery, The Ohio State University, Columbus, OH 43210, USA; James Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. FAU - Kim, Hyunggee AU - Kim H AD - School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Republic of Korea. Electronic address: hg-kim@korea.ac.kr. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140728 PL - Ireland TA - Cancer Lett JT - Cancer letters JID - 7600053 RN - 0 (Cytokines) RN - 0 (NF-kappa B) RN - 0 (RANK Ligand) RN - 0 (TNFSF11 protein, human) SB - IM MH - Animals MH - Astrocytes/*physiology MH - Brain Neoplasms/*metabolism/mortality/pathology MH - Cell Line, Tumor MH - Cell Movement MH - Cytokines/*physiology MH - Glioblastoma/*metabolism/mortality/pathology MH - Humans MH - Kaplan-Meier Estimate MH - Mice MH - Mice, Inbred BALB C MH - Mice, Nude MH - NF-kappa B/metabolism MH - Neoplasm Invasiveness MH - Neoplasm Transplantation MH - RANK Ligand/*physiology MH - Signal Transduction MH - Tumor Microenvironment OTO - NOTNLM OT - Astrocyte OT - Glioblastoma OT - RANKL signaling OT - Tumor-invasive microenvironment EDAT- 2014/08/01 06:00 MHDA- 2014/11/12 06:00 CRDT- 2014/08/01 06:00 PHST- 2014/05/12 00:00 [received] PHST- 2014/07/14 00:00 [accepted] PHST- 2014/08/01 06:00 [entrez] PHST- 2014/08/01 06:00 [pubmed] PHST- 2014/11/12 06:00 [medline] AID - S0304-3835(14)00399-1 [pii] AID - 10.1016/j.canlet.2014.07.034 [doi] PST - ppublish SO - Cancer Lett. 2014 Oct 28;353(2):194-200. doi: 10.1016/j.canlet.2014.07.034. Epub 2014 Jul 28.