The impact of metabolic stress induced by obesity on the bone marrow melanoma niche is largely unknown. Here we employed diet induced obese mice model, where mice received high-fat (HFD) or normal diet (ND) for 6 weeks before challenge with B16F10 melanoma cells. Tumor size, bone loss and osteoclasts numbers were assessed histologically in the tibial bones. For defining the molecular pathway, osteopontin knock-out mice, interleukin 6 neutralizing antibody or Janus kinase 2 inhibition were carried out in the same model. Mechanistic studies such as adipocyte-melanoma co-cultures for defining adipocyte induced changes of tumor cell proliferation and expression profiles were also performed. As results, HFD enhanced melanoma burden in bone by increasing tumor area and osteoclast numbers. This process was associated with higher numbers of bone marrow adipocytes expressing IL-6 in direct vicinity to tumor cells. Inhibition of IL-6 or of downstream JAK2 blocked HFD-induced tumor progression. Furthermore, the phenotypic changes of melanoma cells triggered macrophage and osteoclast accumulation accompanied by increased osteopontin expression. Osteopontin triggered osteoclastogenesis and also exerted a positive feedback loop to tumor cells, which was abrogated in its absence. Metabolic stress by HFD promotes melanoma growth in the bone marrow by an increase in bone marrow adipocytes and IL-6-JAK2-osteopontin mediated activation of tumor cells and osteoclast differentiation.
[1]Univ Erlangen Nurnberg, Dept Internal Med 3, Erlangen, Germany.
[2]Fudan Univ, Minhang Dist Cent Hosp, Shanghai 200433, Peoples R China.
[3]Fudan Univ, Zhongshan Hosp, Dept Thorac Surg, Shanghai 200433, Peoples R China.
[4]Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Dept Rheumatol, Shanghai 200030, Peoples R China.
[5]Friedrich Alexander Univ Erlangen Nuremberg, Univ Med Ctr Erlangen, Inst Radiol, Erlangen, Germany.
(8.0+极速模式)