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Neighboring adipocytes participate in the bone marrow microenvironment of multiple myeloma cells

Leukemia volume 21, pages 1580–1584 (2007)Cite this article

Multiple myeloma (MM) is a hematological malignancy, characterized by the accumulation of monoclonal plasma cells in the bone marrow (BM). MM disease progression has been recently recognized as the result of an evolving crosstalk between different cell types within the BM. Although genetically abnormal plasma cells define the tumor compartment itself, the surrounding and interwoven stroma provides the supporting framework of the tumor. This framework includes extracellular matrix proteins, secreted growth factors and cellular interactions with fibroblasts, macrophages, endothelial cells, osteoblasts and osteoclasts.1 Little attention has been given to another cell type present in the BM cavity: namely the adipocyte. These are absent in the BM of a new-born individual; however, their number increases with advancing age, resulting in adipocytic deposits occupying up to 70% of the BM cavity in elderly persons. MM is typically a disease of the elderly with a median age of diagnosis of 65 years and the incidence increases with age. Knowing that with advancing age, the BM cavity is filled with adipocytes and that MM cells closely interact with their neighboring cells, we assumed functional interactions between BM adipocytes and MM cells. We studied these interactions using the 5T33MM model and the human MM5.1 cell line. In this study, we further tried to characterize the secreted cytokines and explored the potential role of leptin in mediating the effects of adipocytes. We finally evaluated the expression of leptin receptor on both murine and human MM cells and tried to correlate this with different clinical parameters.

From the observation that MM cells, at interstitial disease stages, can be found in close contact with adipocytes, functional interactions between these cells are reasonable and prompted us to start in vitro tests. The murine BM adipocytic cell line 14F1.1 (obtained from Professor Zipori D, Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel) and primary isolated human adipocytes were used. The 14F1.1 cells initially have a fibroblastoid morphology, but after reaching confluence they start to differentiate towards adipocytes.2 Addition of an adipogenic cocktail (2 μ M insulin, 0.5 mM 3-isobutyl-1-methylxanthine and 1 μ M dexamethasone) finally results in a homogenous fat cell population (95% of the cells containing large Oil Red O-positive lipid droplets). For confirmation with human MM cells, primary cultured BM adipocytic cells were used. These were isolated from femoral BM samples, obtained from patients undergoing hip surgery at the CHU Hospital (Liege, Belgium) after giving informed consent. Cells from femoral BM biopsies were isolated by digestion with bacterial collagenase for 1 h 30 min at 37°C. Floating adipocytes were separated from hematopoietic and stromal cells (sedimented cells) by centrifugation for 10 min at 700 r.p.m. and then filtered on a 200 μm membrane and washed twice with phosphate-buffered saline.3

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Acknowledgements

This work was financially supported by the Onderzoeksraad-VUB, the Fund for Scientific Research-Vlaanderen (FWO-Vlaanderen), the Belgian Federation against Cancer, the Association for International Cancer Research and Willy Gepts Foundation(AZ-VUB). K Vanderkerken is a post-doctoral fellow of FWO-Vlaanderen. We also thank Angelo Willems and Carine Seynaeve for excellent technical assistance.

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Authors and Affiliations

  1. Laboratory of Hematology and Immunology, Vrije Universiteit Brussel, Brussels, Belgium

    J Caers, S Deleu, E Van Valckenborgh, E De Bruyne, I Van Riet, B Van Camp & K Vanderkerken

  2. Laboratory of Histology and Cytology, Université de Liege, Liege, Belgium

    Z Belaid & M-P DeFresne

  3. Department of Pathology, Antwerp University, Antwerp, Belgium

    H De Raeve

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  1. J Caers
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  2. S Deleu
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Correspondence to K Vanderkerken.

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Caers, J., Deleu, S., Belaid, Z. et al. Neighboring adipocytes participate in the bone marrow microenvironment of multiple myeloma cells. Leukemia 21, 1580–1584 (2007). https://doi.org/10.1038/sj.leu.2404658

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