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

Details

Serval ID
serval:BIB_D30E2A3AC414
Type
Article: article from journal or magazin.
Collection
Publications
Title
C-met inhibition blocks bone metastasis development induced by renal cancer stem cells.
Journal
Oncotarget
Author(s)
D'Amico L., Belisario D., Migliardi G., Grange C., Bussolati B., D'Amelio P., Perera T., Dalmasso E., Dalle Carbonare L., Godio L., Comoglio P., Trusolino L., Ferracini R., Roato I.
ISSN
1949-2553 (Electronic)
ISSN-L
1949-2553
Publication state
Published
Issued date
19/07/2016
Peer-reviewed
Oui
Volume
7
Number
29
Pages
45525-45537
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
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.
Keywords
Animals, Antineoplastic Agents/pharmacology, Bone Neoplasms/metabolism, Bone Neoplasms/secondary, Carcinoma, Renal Cell/metabolism, Carcinoma, Renal Cell/secondary, Cell Line, Tumor, Enzyme Inhibitors/pharmacology, Humans, Kidney Neoplasms/metabolism, Kidney Neoplasms/pathology, Male, Mice, Mice, Inbred NOD, Mice, SCID, Neoplastic Stem Cells/metabolism, Neoplastic Stem Cells/pathology, Proto-Oncogene Proteins c-met/metabolism, Pyrazoles/pharmacology, Pyridazines/pharmacology, Xenograft Model Antitumor Assays, CCL20, bone metastasis, c-MET, cancer stem cells, renal cancer
Pubmed
Web of science
Open Access
Yes
Create date
13/01/2020 15:58
Last modification date
14/01/2020 6:26
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