dual-effects-melanoma-cell-derived-factors-on-bone-marrow-adipocytes

Dual Effects of Melanoma Cell-derived Factors on Bone Marrow Adipocytes Differentiation

The crosstalk between bone marrow adipocytes and tumor cells may play a critical role in the process of bone metastasis. A variety of methods are ...

Fudan University

Cutaneous vasculitis, interstitial pneumonia with crazy-paving appearance on high-resolution computed tomography, and repeated positive perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) are rarely found together in patients with inflammatory bowel disease in the existing literature. We report the case of a Chinese patient previously diagnosed with cutaneous vasculitis and interstitial pneumonia, who presented with acute pain and mass in his right lower quadrant a couple of years later. The terminal ileum biopsy and postoperative pathology confirmed Crohn's disease (CD). 

Cutaneous Vasculitis, Interstitial Pneumonia with Crazy-Paving Appearance, and Positive pANCA in a Patient with Severe Crohn's Disease.

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.

High fat diet increases melanoma cell growth in the bone marrow by inducing osteopontin and interleukin 6.

Bone marrow (BM) adipocytes are abundant in BM and may be involved in the process of bone metastasis. However, their behaviors in metastatic BM niches during bone metastasis have not been fully explored. In this study, intracardiac transplantation of B16-F10 melanoma cells into immunocompetent C57BL/6 mice was performed. Tibial marrow sections were stained with hematoxylin and eosin, Masson's trichrome, tartrate-resistant acid phosphatase, and fatty acid-binding protein 4 (FABP4) and analyzed using a histomorphometric system. The results showed that the number of BM adipocytes rapidly increased in melanoma metastatic BM niches, which were in direct contact with metastasizing melanoma cells and acted as a tumor stromal population in the BM-melanoma niche. Melanoma cell-derived factors could enhance BM adipogenesis, which promotes melanoma cell proliferation and cell cycle transitions. Moreover, BM adipocytes might aid in the modification of the osteolytic BM microenvironment. These results indicate that an increase in the number of BM adipocytes in a metastatic BM niche may facilitate melanoma cell colonization and growth in BM. BM adipocytes might therefore support the development of bone metastases.

Guang-Liang Chen

Department of Medical Oncology,
Fudan University Shanghai Cancer Center; Department of Oncology,
Shanghai Medical College,
Department of Medical Oncology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College

Fudan University

Dual Effects of Melanoma Cell-derived Factors on Bone Marrow Adipocytes Differentiation