TNF[alpha] promotes osteosarcoma progression by maintaining tumor cells in an undifferentiated state
Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, en maintenant les cellules tumorales dans un état indifférencié, le facteur TNF-alpha favorise la progression d'un ostéosarcome
Résumé en anglais
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 TNF[alpha] 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 TNF[alpha]-deficient mice. AX cells have the capacity to undergo osteoblastic differentiation; however, that activity was significantly inhibited by TNF[alpha] treatment, suggesting that TNF[alpha] maintains AX cells in an undifferentiated state. TNF[alpha] inhibition of AX cell osteoblastic differentiation occurred through ERK activation, and a pharmacological TNF[alpha] 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-1[alpha]/IL-1[beta] doubly deficient mice. We found that both TNF[alpha] 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 TNF[alpha]/IL-1 and ERK may represent therapeutic targets for osteosarcoma.
