Prostate cancer (PCa) is the most frequent malignancy in older men with a high propensity for bone metastases. Characteristically, PCa causes osteosclerotic lesions as a result of disrupted bone remodeling. Extracellular vesicles (EVs) participate in PCa progression by conditioning the pre-metastatic niche. However, how EVs mediate the cross-talk between PCa cells and osteoprogenitors in the bone microenvironment remains poorly understood. We found that EVs derived from murine PCa cell line RM1-BM increased metabolic activity, vitality, and cell proliferation of osteoblast precursors by >60%, while significantly impairing mineral deposition (−37%). The latter was further confirmed in two complementary in vivo models of ossification. Accordingly, gene and protein set enrichments of osteoprogenitors exposed to EVs displayed significant downregulation of osteogenic markers and upregulation of proinflammatory factors. Additionally, transcriptomic profiling of PCa-EVs revealed the abundance of three microRNAs, miR-26a-5p, miR-27a-3p, and miR-30e-5p involved in the suppression of BMP-2-induced osteogenesis in vivo, suggesting the critical role of these EV-derived miRNAs in PCa-mediated suppression of osteoblast activity. Taken together, our results indicate the importance of EV cargo in cancer-bone cross-talk in vitro and in vivo and suggest that exosomal miRNAs may contribute to the onset of osteosclerotic bone lesions in PCa.
|Journal||International journal of molecular sciences|
|Publication status||Published - 24 Jan 2022|
DFG Classification of Subject Areas according to Review Boards
Subject groups, research areas, subject areas according to Destatis
Sustainable Development Goals
ASJC Scopus subject areas
- Bone metastases, Extracellular vesicles, MiRNA, Osteoprogenitors, Prostate cancer, MicroRNAs/genetics, Prostatic Neoplasms/genetics, Cell Proliferation, Tumor Microenvironment, Male, Exosome Multienzyme Ribonuclease Complex/genetics, Extracellular Vesicles/metabolism, Mesenchymal Stem Cells, Exosomes/genetics, Gene Expression Regulation, Neoplastic/genetics, Gene Expression Profiling/methods, Bone and Bones/metabolism, Mice, Inbred C57BL, Cell Communication, Osteoblasts/physiology, Transcriptome/genetics, Animals, Cell Line, Tumor, Mice, Gene Expression/genetics, Osteogenesis