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@ARTICLE{Liu:127963,
author = {L. Liu$^*$ and E. Aleksandrowicz$^*$ and P. Fan$^*$ and F.
Schönsiegel$^*$ and Y. Zhang$^*$ and H. Sähr and J.
Gladkich$^*$ and J. Mattern$^*$ and D. Depeweg and B. Lehner
and J. Fellenberg and I. Herr$^*$},
title = {{E}nrichment of c-{M}et+ tumorigenic stromal cells of giant
cell tumor of bone and targeting by cabozantinib.},
journal = {Cell death $\&$ disease},
volume = {5},
number = {10},
issn = {2041-4889},
address = {London [u.a.]},
publisher = {Nature Publishing Group},
reportid = {DKFZ-2017-03985},
pages = {e1471},
year = {2014},
abstract = {Giant cell tumor of bone (GCTB) is a very rare tumor
entity, which is little examined owing to the lack of
established cell lines and mouse models and the restriction
of available primary cell lines. The stromal cells of GCTB
have been made responsible for the aggressive growth and
metastasis, emphasizing the presence of a cancer stem cell
population. To identify and target such tumor-initiating
cells, stromal cells were isolated from eight freshly
resected GCTB tissues. Tumorigenic properties were examined
by colony and spheroid formation, differentiation,
migration, MTT
(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide) assay, immunohistochemistry, antibody protein
array, Alu in situ hybridization, FACS analysis and
xenotransplantation into fertilized chicken eggs and mice. A
sub-population of the neoplastic stromal cells formed
spheroids and colonies, differentiated to osteoblasts,
migrated to wounded regions and expressed the metastasis
marker CXC-chemokine receptor type 4, indicating
self-renewal, invasion and differentiation potential.
Compared with adherent-growing cells, markers for
pluripotency, stemness and cancer progression, including the
CSC surface marker c-Met, were enhanced in spheroidal cells.
This c-Met-enriched sub-population formed xenograft tumors
in fertilized chicken eggs and mice. Cabozantinib, an
inhibitor of c-Met in phase II trials, eliminated CSC
features with a higher therapeutic effect than standard
chemotherapy. This study identifies a c-Met(+) tumorigenic
sub-population within stromal GCTB cells and suggests the
c-Met inhibitor cabozantinib as a new therapeutic option for
targeted elimination of unresectable or recurrent GCTB.},
keywords = {Anilides (NLM Chemicals) / Biomarkers, Tumor (NLM
Chemicals) / Pyridines (NLM Chemicals) / cabozantinib (NLM
Chemicals) / Proto-Oncogene Proteins c-met (NLM Chemicals)},
cin = {G403},
ddc = {570},
cid = {I:(DE-He78)G403-20160331},
pnm = {317 - Translational cancer research (POF3-317)},
pid = {G:(DE-HGF)POF3-317},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:25321478},
pmc = {pmc:PMC4237261},
doi = {10.1038/cddis.2014.440},
url = {https://inrepo02.dkfz.de/record/127963},
}