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

// Lucia D’Amico 1, 2 , Dimas Belisario 2 , Giorgia Migliardi 3 , Cristina Grange 4 , Benedetta Bussolati 5 , Patrizia D’Amelio 6 , Timothy Perera 7 , Ettore Dalmasso 8 , Luca Dalle Carbonare 9 , Laura Godio 10 , Paolo Comoglio 3 , Livio Trusolino 3 , Riccardo Ferracini 11 , Ilaria Roato 2 1 Department of Biomedicine, Cancer Immunology, University of Basel, Basel, Switzerland 2 CeRMS, A.O. Citta della Salute e della Scienza, Torino, Italy 3 IRCC, Institute for Cancer Research and Treatment, Candiolo, Torino, Italy 4 Department of Medical Sciences, University of Turin, Torino, Italy 5 Department of Molecular Biotechnology and Health Science, Molecular Biotechnology Center, University of Turin, Torino, Italy 6 Gerontology Section, Department of Medical Sciences, University of Torino, Torino, Italy 7 Janssen Research and Development, Beerse, Belgium 8 Urology Section, A.O. Citta della Salute e della Scienza, Torino, Italy 9 Clinic of Internal Medicine, Section D, Policlinico G.B. Rossi Verona, Verona, Italy 10 Department of Pathology, A.O. Citta della Salute e della Scienza, Torino, Italy 11 Department 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.