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@ARTICLE{Vallet:130705,
      author       = {S. Vallet and M. H. Bashari and F.-J. Fan and S. Malvestiti
                      and A. Schneeweiss and P. Wuchter and D. Jäger$^*$ and K.
                      Podar$^*$},
      title        = {{P}re-{O}steoblasts {S}timulate {M}igration of {B}reast
                      {C}ancer {C}ells via the {HGF}/{MET} {P}athway.},
      journal      = {PLoS one},
      volume       = {11},
      number       = {3},
      issn         = {1932-6203},
      address      = {Lawrence, Kan.},
      publisher    = {PLoS},
      reportid     = {DKFZ-2017-05783},
      pages        = {e0150507 -},
      year         = {2016},
      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.},
      keywords     = {2-fluoro-N-methyl-4-(7-(quinolin-6-yl-methyl)imidazo(1,2-b)(1,2,4)triazin-2-yl)benzamide
                      (NLM Chemicals) / Benzamides (NLM Chemicals) / Bridged
                      Bicyclo Compounds, Heterocyclic (NLM Chemicals) / Culture
                      Media, Conditioned (NLM Chemicals) / HGF protein, human (NLM
                      Chemicals) / RNA, Small Interfering (NLM Chemicals) /
                      Hepatocyte Growth Factor (NLM Chemicals) / MET protein,
                      human (NLM Chemicals) / Proto-Oncogene Proteins c-met (NLM
                      Chemicals)},
      cin          = {G010 / D120},
      ddc          = {500},
      cid          = {I:(DE-He78)G010-20160331 / I:(DE-He78)D120-20160331},
      pnm          = {314 - Tumor immunology (POF3-314)},
      pid          = {G:(DE-HGF)POF3-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:26934743},
      pmc          = {pmc:PMC4774929},
      doi          = {10.1371/journal.pone.0150507},
      url          = {https://inrepo02.dkfz.de/record/130705},
}