C-met inhibition blocks bone metastasis development induced by renal cancer stem cells

Lucia D'Amico, Dimas Belisario, Giorgia Migliardi, Cristina Grange, Benedetta Bussolati, Patrizia D'Amelio, Timothy Perera, Ettore Dalmasso, Luca Dalle Carbonare, Laura Godio, Paolo Comoglio, Livio Trusolino, Riccardo Ferracini, Ilaria Roato

Research output: Contribution to journalArticle

Abstract

Cancer stem cells (CSCs) are key players in bone metastasis. In some renal tumors CSCs overexpress the HGF receptor c-MET, speculating that c-MET targeting could lead to bone metastasis inhibition. To address this hypothesis we isolated renal CD105+/CD24-CSCs, expressing c-MET receptor from a primary renal carcinoma. Then, to study their ability to metastasize to bone, we injected renal CSCs in NOD/ SCID mice implanted with a human bone and we tested the effect of a c-MET inhibitor (JNJ-38877605) on bone metastasis development. JNJ-38877605 inhibited the formation of metastases at bone implant site. We showed that JNJ-38877605 inhibited the activation of osteoclasts induced by RCC stem cells and it stimulated osteoblast activity, finally resulting in a reduction of bone turnover consistent with the inhibition of bone metastases. We measured the circulating levels of osteotropic factors induced by RCC stem cells in the sera of mice treated with c-Met inhibitor, showing that IL-11 and CCL20 were reduced in mice treated with JNJ-38877605, strongly supporting the involvement of c-MET in the regulation of this process. To address the clinical relevance of c-MET upregulation during tumor progression, we analysed c-MET in renal cancer patients detecting an increased expression in the bone metastatic lesions by IHC. Then, we dosed CCL20 serum levels resulting significantly increased in patients with bone metastases compared to non-metastatic ones. Collectively, our data highlight the importance of the c-MET pathway in the pathogenesis of bone metastases induced by RCC stem cells in mice and humans.

Original languageEnglish
Pages (from-to)45525-45537
Number of pages13
JournalOncotarget
Volume7
Issue number29
DOIs
Publication statusPublished - 2016

Keywords

  • Bone metastasis
  • C-MET
  • Cancer stem cells
  • CCL20
  • Renal cancer

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    D'Amico, L., Belisario, D., Migliardi, G., Grange, C., Bussolati, B., D'Amelio, P., Perera, T., Dalmasso, E., Carbonare, L. D., Godio, L., Comoglio, P., Trusolino, L., Ferracini, R., & Roato, I. (2016). C-met inhibition blocks bone metastasis development induced by renal cancer stem cells. Oncotarget, 7(29), 45525-45537. https://doi.org/10.18632/oncotarget.9997