C-met inhibition blocks bone metastasis development induced by renal cancer stem cells.
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.
Cancer Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland.|CeRMS, A.O. Città della Salute e della Scienza, Torino, Italy.
Lucia
L
D'Amico
Cancer Immunology, Department of Biomedicine, University of Basel, Basel, Switzerland.
Dimas
D
Belisario
IRCC, Institute for Cancer Research and Treatment, Candiolo, Torino, Italy.
Giorgia
G
Migliardi
Department of Medical Sciences, University of Turin, Torino, Italy.
Cristina
C
Grange
Molecular Biotechnology and Health Science, Molecular Biotechnology Center, University of Turin, Torino, Italy.
Benedetta
B
Bussolati
Gerontology Section, Department of Medical Sciences, University of Torino, Torino, Italy.
Patrizia
P
D'Amelio
Janssen Research and Development, Beerse, Belgium.
Timothy
T
Perera
Urology Section, A.O. Città della Salute e della Scienza, Torino, Italy.
Ettore
E
Dalmasso
Clinic of Internal Medicine, Section D, Policlinico G.B. Rossi Verona, Verona, Italy.
Luca
L
Dalle Carbonare
Department of Pathology, A.O. Città della Salute e della Scienza, Torino, Italy.
Laura
L
Godio
IRCC, Institute for Cancer Research and Treatment, Candiolo, Torino, Italy.
Paolo
P
Comoglio
IRCC, Institute for Cancer Research and Treatment, Candiolo, Torino, Italy.
Livio
L
Trusolino
Department of Orthopaedic Oncology, CTO Hospital, Torino, Italy.
Riccardo
R
Ferracini
CeRMS, A.O. Città della Salute e della Scienza, Torino, Italy.
Ilaria
I
Roato
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary*; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000556:secondary*; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C000599304:JNJ38877605; D011720:Pyrazoles; D011724:Pyridazines; D019859:Proto-Oncogene Proteins c-met
CCL20; bone metastasis; c-MET; cancer stem cells; renal cancer