Exosomal miRNAs from Prostate Cancer Impair Osteoblast Function in Mice

International Journal of Molecular Sciences

Thomas Kurth¹  Dimitra Alexopoulou²  Andreas Dahl²  Stefanie Conrad³  Lorenz C. Hofbauer³  Martina Rauner³  Giulia Furesi³  Stefan Kalkhof⁴  Johannes R. Schmidt⁴  Hanna Taipaleenmäki⁵  Antonio Miguel de Jesus Domingues⁶  Christine Hofbauer⁷  Matthias Hackl⁸ 

[1] Center for Molecular and Cellular Bioengineering (CMCB), Technology Platform, EM and Histology Facility, TU Dresden, 01307 Dresden, Germany;DRESDEN-Concept Genome Center, DFG NGS Competence Center, c/o Center for Molecular and Cellular Bioengineering (CMCB), Technical University of Dresden, 01307 Dresden, Germany;Department of Medicine III & Center for Healthy Aging, Technical University of Dresden, 01307 Dresden, Germany;Department of Preclinical Development and Validation, Fraunhofer Institute for Cell Therapy and Immunology IZI, 04103 Leipzig, Germany;Institute of Musculoskeletal Medicine (IMM), Musculoskeletal University Center Munich (MUM), University Hospital, LMU Munich, 82152 Planegg-Martinsried, Germany;Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany;National Center for Tumor Diseases, Technical University of Dresden, 01307 Dresden, Germany;TAmiRNA GmbH, 1110 Vienna, Austria;

关键词: bone metastases;    prostate cancer;    osteoprogenitors;    extracellular vesicles;    miRNA;   

DOI  :  10.3390/ijms23031285

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown