Abstract
Extracellular vesicles (EVs) are emerging as mediators of a range of pathological processes, including cancer. However, their role in bone metastases has been poorly explored. We investigated EV-mediated effects of osteotropic breast cancer cells (MDA-MB-231) on bone resident cells and endothelial cells. Pretreatment of osteoblasts with conditioned medium (CM) of MDA-MB-231 (MDA) cells promoted pro-osteoclastogenic and pro-angiogenic effects by osteoblast EVs (OB-EVs), as well as an increase of RANKL-positive OB-EVs. Moreover, when treating osteoblasts with MDA-EVs, we observed a reduction of their number, metabolic activity, and alkaline phosphatase (Alp) activity. MDA-EVs also reduced transcription of Cyclin D1 and of the osteoblast-differentiating genes, while enhancing the expression of the pro-osteoclastogenic factors Rankl, Lcn2, Il1b, and Il6. Interestingly, a cytokine array on CM from osteoblasts treated with MDA-EVs showed an increase of the cytokines CCL3, CXCL2, Reg3G, and VEGF, while OPG and WISP1 were downregulated. MDA-EVs contained mRNAs of genes involved in bone metabolism, as well as cytokines, including PDGF-BB, CCL3, CCL27, VEGF, and Angiopoietin 2. In line with this profile, MDA-EVs increased osteoclastogenesis and in vivo angiogenesis. Finally, intraperitoneal injection of MDA-EVs in mice revealed their ability to reach the bone microenvironment and be integrated by osteoblasts and osteoclasts. In conclusion, we showed a role for osteoblast-derived EVs and tumor cell–derived EVs in the deregulation of bone and endothelial cell physiology, thus fueling the vicious cycle induced by bone tumors. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research
Original language | English |
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Pages (from-to) | 396-412 |
Number of pages | 17 |
Journal | J. Bone Miner. Res. |
Volume | 35 |
Issue number | 2 |
DOIs | |
Publication status | Published - 2020 |
Keywords
- CANCER
- CELL/TISSUE SIGNALING - ENDOCRINE PATHWAYS
- CELL/TISSUE SIGNALING - PARACRINE PATHWAYS
- CELLS OF BONE
- CYTOKINES
- OSTEOBLASTS
- OSTEOCLASTS
- OTHER
- TUMOR-INDUCED BONE DISEASE
- alkaline phosphatase
- angiopoietin 2
- collagen 1a1
- collagen type 1
- cutaneous T cell attracting chemokine
- CXCL2 chemokine
- cyclin D1
- estrogen receptor
- gamma interferon inducible protein 10
- inducible nitric oxide synthase
- interleukin 1beta
- interleukin 6
- macrophage inflammatory protein 1alpha
- macrophage inflammatory protein 3alpha
- messenger RNA
- neutrophil gelatinase associated lipocalin
- osteocalcin
- osteoclast differentiation factor
- pancreatitis associated protein
- platelet derived growth factor BB
- transcription factor osterix
- transcription factor RUNX2
- transforming growth factor beta1
- unclassified drug
- vasculotropin
- 4T1 cell line
- angiogenesis
- animal experiment
- animal model
- animal tissue
- Article
- bone cell
- bone metabolism
- breast cancer
- cell count
- cell differentiation
- chondrocyte
- comparative study
- controlled study
- cytokine release
- down regulation
- endothelium cell
- enzyme activity
- enzyme linked immunosorbent assay
- ex vivo study
- exosome
- female
- histochemistry
- human
- human cell
- in vitro study
- in vivo study
- male
- mouse
- mRNA expression level
- MTT assay
- nonhuman
- osteoblast
- osteoclast
- osteoclastogenesis
- osteoporosis
- transmission electron microscopy
- Western blotting