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, Serkin Park

Research output: Contribution to journalArticle

9 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

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Bone Neoplasms
Osteolysis
Osteoblasts
Prostatic Neoplasms
Macrophage Colony-Stimulating Factor
Neoplasm Metastasis
Growth
Hepatocyte Growth Factor
Bone Development
Somatomedins
Osteogenesis
Bone and Bones
Vascular Endothelial Growth Factor Receptor-2
Neoplasms
Conditioned Culture Medium
Vascular Endothelial Growth Factor A
Transcriptional Activation
Phosphotransferases
Ligands
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Dual targeting c-met and VEGFR2 in osteoblasts suppresses growth and osteolysis of prostate cancer bone metastasis. / Lee, Changki; Whang, Young Mi; Campbell, Preston; Mulcrone, Patrick L.; Elefteriou, Florent; Cho, Sun Wook; Park, Serkin.

In: Cancer Letters, Vol. 414, 01.02.2018, p. 205-213.

Research output: Contribution to journalArticle

Lee, Changki ; Whang, Young Mi ; Campbell, Preston ; Mulcrone, Patrick L. ; Elefteriou, Florent ; Cho, Sun Wook ; Park, Serkin. / Dual targeting c-met and VEGFR2 in osteoblasts suppresses growth and osteolysis of prostate cancer bone metastasis. In: Cancer Letters. 2018 ; Vol. 414. pp. 205-213.
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