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

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34 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)4236-4241
Number of pages6
JournalOncogene
Volume33
Issue number33
DOIs
Publication statusPublished - 14-08-2014
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Mori, T., Sato, Y., Miyamoto, K., Kobayashi, T., Shimizu, T., Kanagawa, H., Katsuyama, E., Fujie, A., Hao, W., Tando, T., Iwasaki, R., Kawana, H., Morioka, H., Matsumoto, M., Saya, H., Toyama, Y., & Miyamoto, T. (2014). TNFα promotes osteosarcoma progression by maintaining tumor cells in an undifferentiated state. Oncogene, 33(33), 4236-4241. https://doi.org/10.1038/onc.2013.545