TNFα promotes osteosarcoma progression by maintaining tumor cells in an undifferentiated state

T. Mori, Y. Sato, K. Miyamoto, T. Kobayashi, T. Shimizu, H. Kanagawa, E. Katsuyama, A. Fujie, W. Hao, T. Tando, R. Iwasaki, H. Kawana, H. Morioka, M. Matsumoto, H. Saya, Y. Toyama, T. Miyamoto

研究成果: Article査読

40 被引用数 (Scopus)

抄録

Chronic inflammation is frequently associated with tumorigenesis in elderly people. By contrast, young people without chronic inflammation often develop tumors considered independent of chronic inflammation but driven instead by mutations. Thus, whether inflammation has a significant role in tumor progression in tumors driven by mutations remains largely unknown. Here we show that TNFα is required for the tumorigenesis of osteosarcoma, the most common tumor in children and adolescents. We show that transplantation of AX osteosarcoma cells, which harbor mutations driving c-Myc overexpression and Ink4a-deficiency, in wild-type mice promotes lethal tumorigenesis accompanied by ectopic bone formation and multiple metastases, phenotypes seen in osteosarcoma patients. Such tumorigenesis was completely abrogated in TNFα-deficient mice. AX cells have the capacity to undergo osteoblastic differentiation; however, that activity was significantly inhibited by TNFα treatment, suggesting that TNFα maintains AX cells in an undifferentiated state. TNFα inhibition of AX cell osteoblastic differentiation occurred through ERK activation, and a pharmacological TNFα inhibitor effectively inhibited both AX cell tumorigenesis and increased osteoblastic gene expression and increased survival of tumor-bearing mice. Lethal tumorigenesis of AX cells was also abrogated in IL-1α/IL-1β doubly deficient mice. We found that both TNFα and IL-1 maintained AX cells in an undifferentiated state via ERK activation. Thus, inflammatory cytokines are required to promote tumorigenesis even in mutation-induced tumors, and TNFα/IL-1 and ERK may represent therapeutic targets for osteosarcoma.

本文言語English
ページ(範囲)4236-4241
ページ数6
ジャーナルOncogene
33
33
DOI
出版ステータスPublished - 2014 8 14

ASJC Scopus subject areas

  • 分子生物学
  • 遺伝学
  • 癌研究

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