Tumoral RANKL activates astrocytes that promote glioma cell invasion through cytokine signaling

Jun Kyum Kim, Xiong Jin, Young Woo Sohn, Xun Jin, Hee Young Jeon, Eun Jung Kim, Seok Won Ham, Hye Min Jeon, So Young Chang, Se Yeong Oh, Jinlong Yin, Sung Hak Kim, Jong Bae Park, Ichiro Nakano, Hyunggee Kim

Research output: Contribution to journalArticlepeer-review

58 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)194-200
Number of pages7
JournalCancer letters
Issue number2
Publication statusPublished - 2014

Bibliographical note

Funding Information:
This study was supported by National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea ( 1020270 to H. Kim), and National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST) ( 2011-0017544 to H. Kim and 2011-0024089 to S.H. Kim). S.Y. Oh is a recipient of research grant supported by Institute of Life Science and Natural Resources, Korea University .

Publisher Copyright:
© 2014 Elsevier Ireland Ltd.


  • Astrocyte
  • Glioblastoma
  • RANKL signaling
  • Tumor-invasive microenvironment

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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