Renal cancer patients often develop particularly destructive bone metastases. In solid tumours, cancer stem cells (CSCs) directly promote bone metastasis, thus therapeutic strategies to block the interaction between CSCs and bone microenvironment are currently under investigation. Since c-MET mediates the interaction between cancer cells and mesenchymal cells of the bone microenvironment, we hypothesised that targeting c-MET will lead to bone metastases inhibition. Renal CD105+ CSCs isolated from human cancer patients were injected in NOD/SCID mice, previously implanted with a small fragment of human bone. After the injection of CSCs, mice were daily treated or not with a c-MET inhibitor (JNJ) for 90 days, then sacrificed. Importantly renal CSCs colonised human implanted bone but not mice bone, leading to a specie-specificity of those cells to metastasize human bone. We then found that the JNJ treatment inhibited metastatisation at bone implant site. We studied the effect of JNJ on osteoclasts (OCs) and osteoblasts (OBs) of the bone implant by histomorphometry, showing that CSCs induced an activation of OCs corresponding to an increase erosion surface, whereas the OB activity diminished with a reduction of the osteoid thickness. The treatment with JNJ restored the normal activity of OCs and OBs, comparable with the control mice. Then we investigated the effect of JNJ on in vitro cultures of human OCs and OBs, to avoid the bone microenvironment interference. JNJ reduced the number of TRAP+ OCs, whereas it did not significantly affect the number of BAP+ OBs. Furthermore, we analysed mice sera by a multi-analyte detection system, showing that IL-11 and CCL20 levels are higher in mice untreated with JNJ than in treated ones, suggesting a role of these molecules in the CSC bone metastatic process. Our results highlight the ability of this c-MET inhibitor to abrogate the bone metastastis formation induced by renal CSCs.
Disclosure: The authors declared no competing interests. This work was supported by the Italian Ministry of Health: Ricerca Sanitaria Finalizzata e Giovani Ricercatori 2009 (GR 2009-1584485).