Oncotarget

Research Papers:

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 and Ilaria Roato _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2016; 7:45525-45537. https://doi.org/10.18632/oncotarget.9997

Metrics: PDF 1522 views  |   HTML 1969 views  |   ?  


Abstract

Lucia D’Amico1,2, Dimas Belisario2, Giorgia Migliardi3, Cristina Grange4, Benedetta Bussolati5, Patrizia D’Amelio6, Timothy Perera7, Ettore Dalmasso8, Luca Dalle Carbonare9, Laura Godio10, Paolo Comoglio3, Livio Trusolino3, Riccardo Ferracini11, Ilaria Roato2

1Department of Biomedicine, Cancer Immunology, University of Basel, Basel, Switzerland

2CeRMS, A.O. Città della Salute e della Scienza, Torino, Italy

3IRCC, Institute for Cancer Research and Treatment, Candiolo, Torino, Italy

4Department of Medical Sciences, University of Turin, Torino, Italy

5Department of Molecular Biotechnology and Health Science, Molecular Biotechnology Center, University of Turin, Torino, Italy

6Gerontology Section, Department of Medical Sciences, University of Torino, Torino, Italy

7Janssen Research and Development, Beerse, Belgium

8Urology Section, A.O. Città della Salute e della Scienza, Torino, Italy

9Clinic of Internal Medicine, Section D, Policlinico G.B. Rossi Verona, Verona, Italy

10Department of Pathology, A.O. Città della Salute e della Scienza, Torino, Italy

11Department of Orthopaedic Oncology, CTO Hospital, Torino, Italy

Correspondence to:

Ilaria Roato, email: ilaria.roato@unito.it

Keywords: bone metastasis, renal cancer, cancer stem cells, c-MET, CCL20

Received: May 01, 2016     Accepted: May 29, 2016     Published: June 14, 2016

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 9997