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Myeloma

Bone marrow fibroblasts parallel multiple myeloma progression in patients and mice: in vitro and in vivo studies

Leukemia volume 28, pages 904–916 (2014)Cite this article

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Abstract

The role of cancer-associated fibroblasts (CAFs) has not been previously studied in multiple myeloma (MM). Here, cytofluorimetric analysis revealed higher proportions of bone marrow (BM) CAFs in patients with active MM (both at diagnosis and relapse) compared with patients in remission or those with monoclonal gammopathy of undetermined significance or deficiency anemia (controls). CAFs from MM patients produced increased levels of transforming growth factor-β, interleukin-6, stromal cell-derived factor-1α, insulin-like growth factor-1, vascular endothelial growth factor and fibroblast growth factor-2 and displayed an activated and heterogeneous phenotype, which supported their origin from resident fibroblasts, endothelial cells and hematopoietic stem and progenitor cells via the endothelial–mesenchymal transition as well as mesenchymal stem cells via the mesenchymal transition, as both of these processes are induced by MM cells and CAFs. Active MM CAFs fostered chemotaxis, adhesion, proliferation and apoptosis resistance in MM cells through cytokine signals and cell-to-cell contact, which were inhibited by blocking CXCR4, several integrins and fibronectin. MM cells also induced the CAFs proliferation. In syngeneic 5T33MM and xenograft mouse models, MM cells induced the expansion of CAFs, which, in turn, promoted MM initiation and progression as well as angiogenesis. In BM biopsies from patients and mice, nests of CAFs were found in close contact with MM cells, suggesting a supportive niche. Therefore, the targeting of CAFs in MM patients may be envisaged as a novel therapeutic strategy.

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Acknowledgements

We are grateful to K De Veirman (Vrije Universiteit Brussels) for help with the cytofluorimetric experiments in syngeneic 5T33 mice. This work was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC); an Investigator Grant (number 10099 to AV); the Special Program Molecular Clinical Oncology 5 per 1000 (number 9965 to AV), Milan; the European Commission’s Seventh Framework Programme (EU FPT7) OVER-MyR (number 278706 to AV and KV) and OPTATIO (number 278570 to DR); and the Ministry of Health (Progetto PRIN 2009 to RR and 2012 to AV), Rome, Italy.

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Authors and Affiliations

  1. Department of Biomedical Sciences and Human Oncology (DIMO), General Pathology Section, Bari, Italy

    M A Frassanito & R Fumarulo

  2. Internal Medicine Section, University of Bari Medical School, Bari, Italy

    L Rao, M Moschetta, R Ria, L Di Marzo, A De Luisi, V Racanelli, I Catacchio, S Berardi, A Basile, F Dammacco & A Vacca

  3. Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium

    E Menu & K Vanderkerken

  4. Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy

    S Ruggieri, B Nico & D Ribatti

  5. National Cancer Institute “Giovanni Paolo II”, Bari, Italy

    D Ribatti

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Frassanito, M., Rao, L., Moschetta, M. et al. Bone marrow fibroblasts parallel multiple myeloma progression in patients and mice: in vitro and in vivo studies. Leukemia 28, 904–916 (2014). https://doi.org/10.1038/leu.2013.254

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