Scientific reports, 2019-06, Vol.9 (1), p.8726-12, Article 8726
2019
Details
- Autor(en) / Beteiligte
- Titel
- A Selective FGFR inhibitor AZD4547 suppresses RANKL/M-CSF/OPG-dependent ostoclastogenesis and breast cancer growth in the metastatic bone microenvironment
- Ist Teil von
- Scientific reports, 2019-06, Vol.9 (1), p.8726-12, Article 8726
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2019
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Aberrant activation of fibroblast growth factor receptor (FGFR) signalling contributes to progression and metastasis of many types of cancers including breast cancer. Accordingly, FGFR targeted tyrosine kinase inhibitors (TKIs) are currently under development. However, the efficacy of FGFR TKIs in the bone microenvironment where breast cancer cells most frequently metastasize and also where FGFR is biologically active, has not been clearly investigated. We investigated the FGFR-mediated interactions among cancer and the bone microenvironment stromal cells (osteoblasts and osteoclasts), and also the effects of FGFR inhibition in bone metastasis. We showed that addition of culture supernatant from the MDA-MB-134-VI FGFR-amplified breast cancer cells-activated FGFR siganalling in osteoblasts, including increased expression of RANKL, M-CSF, and osteoprotegerin (OPG). Further in vitro analyses showed that AZD4547, an FGFR TKI currently in clinical trials for breast cancer, decreased RANKL and M-CSF, and subsequently RANKL and M-CSF-dependent osteoclastogenesis of murine bone marrow monocytes. Moreover, AZD4547 suppressed osteoclastogenesis and tumor-induced osteolysis in an orthotopic breast cancer bone metastasis mouse model using FGFR non-amplified MDA-MB-231 cells. Collectively, our results support that FGFR inhibitors inhibit the bone microenvironment stromal cells including osteoblasts and osteoclasts, and effectively suppress both tumor and stromal compartments of bone metastasis.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2045-2322eISSN: 2045-2322DOI: 10.1038/s41598-019-45278-wTitel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6584658
- Format
- –
- Schlagworte
- Animals, Benzamides - pharmacology, Biological activity, Bone cancer, Bone growth, Bone marrow, Bone Neoplasms - drug therapy, Bone Neoplasms - metabolism, Bone Neoplasms - pathology, Bone Neoplasms - secondary, Breast cancer, Breast Neoplasms - drug therapy, Breast Neoplasms - metabolism, Breast Neoplasms - pathology, Cell culture, Clinical trials, Female, Fibroblast growth factor receptors, Humans, Macrophage colony-stimulating factor, Macrophage Colony-Stimulating Factor - metabolism, MCF-7 Cells, Metastases, Metastasis, Mice, Mice, Inbred BALB C, Mice, Nude, Monocytes, Neoplasm Metastasis, Neoplasm Proteins - antagonists & inhibitors, Neoplasm Proteins - metabolism, Osteoblasts, Osteoclastogenesis, Osteoclasts, Osteoclasts - metabolism, Osteoclasts - pathology, Osteolysis, Osteoprotegerin, Osteoprotegerin - metabolism, Piperazines - pharmacology, Protein-tyrosine kinase, Pyrazoles - pharmacology, RANK Ligand - metabolism, Receptor Protein-Tyrosine Kinases - antagonists & inhibitors, Stromal cells, TRANCE protein, Tumor Microenvironment - drug effects, Xenograft Model Antitumor Assays