TY  - JOUR
AU  - Vallet, Sonia
AU  - Bashari, Muhammad Hasan
AU  - Fan, Feng-Juan
AU  - Malvestiti, Stefano
AU  - Schneeweiss, Andreas
AU  - Wuchter, Patrick
AU  - Jäger, Dirk
AU  - Podar, Klaus
TI  - Pre-Osteoblasts Stimulate Migration of Breast Cancer Cells via the HGF/MET Pathway.
JO  - PLoS one
VL  - 11
IS  - 3
SN  - 1932-6203
CY  - Lawrence, Kan.
PB  - PLoS
M1  - DKFZ-2017-05783
SP  - e0150507 -
PY  - 2016
AB  - The occurrence of skeletal metastases in cancer, e.g. breast cancer (BC), deteriorates patient life expectancy and quality-of-life. Current treatment options against tumor-associated bone disease are limited to anti-resorptive therapies and aimed towards palliation. There remains a lack of therapeutic approaches, which reverse or even prevent the development of bone metastases. Recent studies demonstrate that not only osteoclasts (OCs), but also osteoblasts (OBs) play a central role in the pathogenesis of skeletal metastases, partly by producing hepatocyte growth factor (HGF), which promotes tumor cell migration and seeding into the bone. OBs consist of a heterogeneous cell pool with respect to their maturation stage and function. Recent studies highlight the critical role of pre-OBs in hematopoiesis. Whether the development of bone metastases can be attributed to a particular OB maturation stage is currently unknown.Pre-OBs were generated from healthy donor (HD)-derived bone marrow stromal cells (BMSC) as well as the BMSC line KM105 and defined as ALPlow OPNlow RUNX2high OSX high CD166high. Conditioned media (CM) of pre-OBs, but not of undifferentiated cells or mature OBs, enhanced migration of metastatic BC cells. Importantly, HGF mRNA was significantly up-regulated in pre-OBs versus mature OBs, and CM of pre-OBs activated the MET signaling pathway. Highlighting a key role for HGF, CM from HGF-negative pre-OBs derived from the BMSC line HS27A did not support migration of BC cells. Genetically (siMET) or pharmacologically (INCB28060) targeting MET inhibited both HGF- and pre-OB CM- mediated BC cell migration.Our data demonstrate for the first time a role for pre-OBs in mediating HGF/MET- dependent migration of BC cells and strongly support the clinical evaluation of INCB28060 and other MET inhibitors to limit and/or prevent BC-associated bone metastases.
KW  - 2-fluoro-N-methyl-4-(7-(quinolin-6-yl-methyl)imidazo(1,2-b)(1,2,4)triazin-2-yl)benzamide (NLM Chemicals)
KW  - Benzamides (NLM Chemicals)
KW  - Bridged Bicyclo Compounds, Heterocyclic (NLM Chemicals)
KW  - Culture Media, Conditioned (NLM Chemicals)
KW  - HGF protein, human (NLM Chemicals)
KW  - RNA, Small Interfering (NLM Chemicals)
KW  - Hepatocyte Growth Factor (NLM Chemicals)
KW  - MET protein, human (NLM Chemicals)
KW  - Proto-Oncogene Proteins c-met (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:26934743
C2  - pmc:PMC4774929
DO  - DOI:10.1371/journal.pone.0150507
UR  - https://inrepo02.dkfz.de/record/130705
ER  -