High fat diet increases melanoma cell growth in the bone marrow by inducing osteopontin and interleukin 6
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Guang-Liang Chen1,2, Yubin Luo1, Daniel Eriksson1, Xianyi Meng1, Cheng Qian3, Tobias Bäuerle5, Xiao-Xiang Chen4, Georg Schett1, Aline Bozec1
1Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany
2Minhang District Central Hospital, Fudan University, Shanghai, China
3Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
4Department of Rheumatology, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
5Institute of Radiology, University Medical Center Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
Aline Bozec, email: firstname.lastname@example.org
Keywords: bone tumor microenvironment, obesity, melanoma, bone marrow adipocyte, osteopontin
Received: January 27, 2016 Accepted: March 07, 2016 Published: March 30, 2016
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.
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