Dual targeting c-met and VEGFR2 in osteoblasts suppresses growth and osteolysis of prostate cancer bone metastasis

• Published in: Cancer letters 2018-02, Vol.414, p.205-213
• Main Authors: Lee, Changki, Whang, Young Mi, Campbell, Preston, Mulcrone, Patrick L., Elefteriou, Florent, Cho, Sun Wook, Park, Serk In
• Format: Article
• Language: English
• Subjects: Anilides - pharmacology; Animals; Antibiotics; Bone marrow; Bone metastasis; Bone Neoplasms - metabolism; Bone Neoplasms - prevention & control; Bone Neoplasms - secondary; Breast cancer; c-Met; Cancer therapies; Cell growth; Cell Line; Cell Line, Tumor; Cell Proliferation - drug effects; Cells, Cultured; Enzyme inhibitors; Gene expression; Growth factors; Humans; Kinases; Male; Metastasis; Mice, Nude; NF-κB protein; Osteoblasts; Osteoblasts - drug effects; Osteoblasts - metabolism; Osteolysis - prevention & control; Physiology; Prostate; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Proto-Oncogene Proteins c-met - genetics; Proto-Oncogene Proteins c-met - metabolism; Pyridines - pharmacology; RNA Interference; Rodents; Vascular endothelial growth factor; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - genetics; Vascular Endothelial Growth Factor Receptor-2 - metabolism; VEGFR2; Xenograft Model Antitumor Assays
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2017.11.016

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 NFκB 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. •HGF, VEGF-A and IGF1 increase M-CSF and RANKL in osteoblasts of the bone metastasis.•HGF, VEGF-A and IGF1 induce osteoclastogenesis via activation of osteoblasts.•A c-Met/VEGFR2 inhibitor suppresses osteoblasts and subsequent osteoclastogenesis.•Targeting c-Met and VEGFR2 in osteoblast suppresses prostate cancer bone metastasis.•Osteoblasts are promising stromal cell target for the treatment of bone metastasis.