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- 검색키워드
- 저자 : Elefteriou, Florent (검색결과 1 건)
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Lee, Changki,Whang, Young Mi,Campbell, Preston,Mulcrone, Patrick L.,Elefteriou, Florent,Cho, Sun Wook,Park, Serk In Elsevier 2018 Cancer letters Vol.414 No.-
<P><B>Abstract</B></P> <P>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. <I>In vivo</I> 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.</P> <P><B>Highlights</B></P> <P> <UL> <LI> HGF, VEGF-A and IGF1 increase M-CSF and RANKL in osteoblasts of the bone metastasis. </LI> <LI> HGF, VEGF-A and IGF1 induce osteoclastogenesis via activation of osteoblasts. </LI> <LI> A c-Met/VEGFR2 inhibitor suppresses osteoblasts and subsequent osteoclastogenesis. </LI> <LI> Targeting c-Met and VEGFR2 in osteoblast suppresses prostate cancer bone metastasis. </LI> <LI> Osteoblasts are promising stromal cell target for the treatment of bone metastasis. </LI> </UL> </P>
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