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

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 TNFa 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 wildtype mice promotes lethal tumorigenesis accompanied by ectopic bone formation and multiple metastases, phenotypes seen in osteosarcoma patients. Such tumorigenesis was completely abrogated in TNFa-deficient mice. AX cells have the capacity to undergo osteoblastic differentiation; however, that activity was significantly inhibited by TNFa treatment, suggesting that TNFa maintains AX cells in an undifferentiated state. TNFa inhibition of AX cell osteoblastic differentiation occurred through ERK activation, and a pharmacological TNFa 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-1a/IL-1b doubly deficient mice. We found that both TNFa 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 TNFa/IL-1 and ERK may represent therapeutic targets for osteosarcoma.

Long Non-Coding RNA Urothelial Carcinoma Associated 1 Promotes Proliferation, Migration and Invasion of Osteosarcoma Cells by Regulating microRNA-182

“…TGF-β and TNF-α have been demonstrated to play tumor promoting roles in osteosarcoma [45,46]. So, in the current study, we further assessed the effects of UCA1 on p53, Rb, iASPP and RECQL, as well as the effects of TGF-β and TNF-α on UCA1 in OS-732 cells.…”

Transient TNF regulates the self-renewing capacity of stem-like label-retaining cells in sphere and skin equivalent models of melanoma

“…For example, TNF was shown to induce the reversible dedifferentiation of melanoma cells [35] and an increased melanocyte number while inhibiting their differentiation-related pigmentation [68]. Similarly, TNF promotes neural stem (NSC) cell proliferation but inhibits their differentiation [69] and maintains osteosarcomas in their undifferentiated state [70]. Additionally, in the hematopoietic system, TNF was shown to have a stimulatory growth effect on hematopoietic stem cells (HSCs) but to negatively regulate the growth of their more mature progenitors in vitro [71].…”

Emerging Cytokine Networks in Osteosarcoma

“…In a murine model of osteosarcoma induced by the transfer of AX mesenchymal cells from INK4a-deficient to wild type mice, TNF-α produced locally by macrophages promoted tumour progression and growth by keeping osteosarcoma cells in an undifferentiated state via extracellular signal-regulated protein kinases (ERK) [63] . Treatment with the TNF-α inhibitor Etanercept® inhibited tumour growth, increased differentiation of osteoblasts and increased survival, highlighting the pro-tumourigenic effect of TNF-α in osteosarcoma [63] . Furthermore, study suggests an association between TNF-α polymorphisms and a higher risk to the development of osteosarcoma [64] .…”