| First Author | Mori T | Year | 2014 |
| Journal | Oncogene | Volume | 33 |
| Issue | 33 | Pages | 4236-41 |
| PubMed ID | 24336323 | Mgi Jnum | J:269406 |
| Mgi Id | MGI:6274815 | Doi | 10.1038/onc.2013.545 |
| Citation | Mori T, et al. (2014) TNFalpha promotes osteosarcoma progression by maintaining tumor cells in an undifferentiated state. Oncogene 33(33):4236-41 |
| abstractText | 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 TNFalpha 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 TNFalpha-deficient mice. AX cells have the capacity to undergo osteoblastic differentiation; however, that activity was significantly inhibited by TNFalpha treatment, suggesting that TNFalpha maintains AX cells in an undifferentiated state. TNFalpha inhibition of AX cell osteoblastic differentiation occurred through ERK activation, and a pharmacological TNFalpha 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-1alpha/IL-1beta doubly deficient mice. We found that both TNFalpha 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 TNFalpha/IL-1 and ERK may represent therapeutic targets for osteosarcoma. |
