title: High fat diet increases melanoma cell growth in the bone marrow by inducing osteopontin and interleukin 6.
abstract: 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.
authors.affiliation: Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.|Minhang District Central Hospital, Fudan University, Shanghai, China.
authors.forename: Guang-Liang
authors.initials: GL
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Eriksson
authors.affiliation: Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Xianyi
authors.initials: X
authors.lastname: Meng
authors.affiliation: Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Qian
authors.affiliation: Institute of Radiology, University Medical Center Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bäuerle
authors.affiliation: Department of Rheumatology, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xiao-Xiang
authors.initials: XX
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.affiliation: Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Aline
authors.initials: A
authors.lastname: Bozec
mesh_terms: D017667:Adipocytes / Q000473:pathology; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary*; D059305:Diet, High-Fat / Q000009:adverse effects*; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D008546:Melanoma, Experimental / Q000378:metabolism / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010010:Osteoclasts / Q000473:pathology; D053495:Osteopontin / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D053495:Osteopontin
keywords: bone marrow adipocyte; bone tumor microenvironment; melanoma; obesity; osteopontin