Dual targeting c-met and VEGFR2 in osteoblasts suppresses growth and osteolysis of prostate cancer bone metastasis
- Authors
- Lee, Changki; Whang, Young Mi; Campbell, Preston; Mulcrone, Patrick L.; Elefteriou, Florent; Cho, Sun Wook; Park, Serk In
- Issue Date
- 1-2월-2018
- Publisher
- ELSEVIER IRELAND LTD
- Keywords
- Prostate cancer; Bone metastasis; Osteoblasts; c-Met; VEGFR2
- Citation
- CANCER LETTERS, v.414, pp.205 - 213
- Indexed
- SCIE
SCOPUS
- Journal Title
- CANCER LETTERS
- Volume
- 414
- Start Page
- 205
- End Page
- 213
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/77406
- DOI
- 10.1016/j.canlet.2017.11.016
- ISSN
- 0304-3835
- Abstract
- Prostate cancer characteristically induces osteoblastic bone metastasis, for which no therapies are available. A dual kinase inhibitor of c-Met and VEGFR-2 (cabozantinib) was shown to reduce prostate cancer growth in bone, with evidence for suppressing osteoblastic activity. However, c-Met and VEGFR2 signaling in osteoblasts in the context of bone metastasis remain unclear. Here we show using cultured osteoblasts that hepatocyte growth factor (HGF) and VEGF-A increased receptor activator of NF kappa B ligand (RANKL) and M-CSF, two essential factors for osteoclastogenesis. Insulin-like growth factor-1 (IGF1) also increased RANKL and M-CSF via c-Met transactivation. The conditioned media from IGF1-, HGF-, or VEGFA-treated osteoblasts promoted osteoclastogenesis that was reversed by inhibiting c-Met and/or VEGFR2 in osteoblasts. In vivo experiments used cabozantinib-resistant prostate cancer cells (PC-3 and C4-2B) to test the effects of c-Met/VEGFR2 inhibition specifically in osteoblasts. Cabozantinib (60 mg/kg, 3 weeks) suppressed tumor growth in bone and reduced expression of RANKL and M-CSF and subsequent tumor-induced osteolysis. Collectively, inhibition of c-Met and VEGFR2 in osteoblasts reduced RANKL and M-CSF expression, and associated with reduction of tumor-induced osteolysis, suggesting that c-Met and VEGFR2 are promising therapeutic targets in bone metastasis. (C) 2017 Elsevier B.V. All rights reserved.
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Collections - Graduate School > Department of Biomedical Sciences > 1. Journal Articles
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