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

Changki Lee, Young Mi Whang, Preston Campbell, Patrick L. Mulcrone, Florent Elefteriou, Sun Wook Cho, Serk In Park

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)205-213
Number of pages9
JournalCancer letters
Volume414
DOIs
Publication statusPublished - 2018 Feb 1

Bibliographical note

Funding Information:
This work was in part supported by the National Research Foundation of Korea (Grants No. 2015R1C1A1A01051508 to S.I.P. and 2016RD1A1B03933826 to Y.M.W.) and the Ministry of Health and Welfare of the Republic of Korea (National R&D Program for Cancer, No. 1720140 to S.W.C. and S.I.P).

Publisher Copyright:
© 2017 Elsevier B.V.

Keywords

  • Bone metastasis
  • Osteoblasts
  • Prostate cancer
  • VEGFR2
  • c-Met

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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