Journal Article

DKFZ-2017-05783

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Pre-Osteoblasts Stimulate Migration of Breast Cancer Cells via the HGF/MET Pathway.

Vallet, S. ; Bashari, M. H. ; Fan, F.-J. ; Malvestiti, S. ; Schneeweiss, A. ; Wuchter, P. ; Jäger, D.DKFZ* ; Podar, K. (Last author)DKFZ*

2016
PLoS Lawrence, Kan.

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Please use a persistent id in citations: doi:10.1371/journal.pone.0150507

Abstract: 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.

Keyword(s): 2-fluoro-N-methyl-4-(7-(quinolin-6-yl-methyl)imidazo(1,2-b)(1,2,4)triazin-2-yl)benzamide ; Benzamides ; Bridged Bicyclo Compounds, Heterocyclic ; Culture Media, Conditioned ; HGF protein, human ; RNA, Small Interfering ; Hepatocyte Growth Factor ; MET protein, human ; Proto-Oncogene Proteins c-met

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Contributing Institute(s):

1. Geschäftsstelle (G010)
2. Angewandte Tumor-Immunität (D120)

Research Program(s):

1. 314 - Tumor immunology (POF3-314) (POF3-314)

Appears in the scientific report 2016

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Database coverage:
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