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000130705 1001_ $$aVallet, Sonia$$b0
000130705 245__ $$aPre-Osteoblasts Stimulate Migration of Breast Cancer Cells via the HGF/MET Pathway.
000130705 260__ $$aLawrence, Kan.$$bPLoS$$c2016
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000130705 520__ $$aThe occurrence of skeletal metastases in cancer, e.g. breast cancer (BC), deteriorates patient life expectancy and quality-of-life. Current treatment options against tumor-associated bone disease are limited to anti-resorptive therapies and aimed towards palliation. There remains a lack of therapeutic approaches, which reverse or even prevent the development of bone metastases. Recent studies demonstrate that not only osteoclasts (OCs), but also osteoblasts (OBs) play a central role in the pathogenesis of skeletal metastases, partly by producing hepatocyte growth factor (HGF), which promotes tumor cell migration and seeding into the bone. OBs consist of a heterogeneous cell pool with respect to their maturation stage and function. Recent studies highlight the critical role of pre-OBs in hematopoiesis. Whether the development of bone metastases can be attributed to a particular OB maturation stage is currently unknown.Pre-OBs were generated from healthy donor (HD)-derived bone marrow stromal cells (BMSC) as well as the BMSC line KM105 and defined as ALPlow OPNlow RUNX2high OSX high CD166high. Conditioned media (CM) of pre-OBs, but not of undifferentiated cells or mature OBs, enhanced migration of metastatic BC cells. Importantly, HGF mRNA was significantly up-regulated in pre-OBs versus mature OBs, and CM of pre-OBs activated the MET signaling pathway. Highlighting a key role for HGF, CM from HGF-negative pre-OBs derived from the BMSC line HS27A did not support migration of BC cells. Genetically (siMET) or pharmacologically (INCB28060) targeting MET inhibited both HGF- and pre-OB CM- mediated BC cell migration.Our data demonstrate for the first time a role for pre-OBs in mediating HGF/MET- dependent migration of BC cells and strongly support the clinical evaluation of INCB28060 and other MET inhibitors to limit and/or prevent BC-associated bone metastases.
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000130705 650_7 $$2NLM Chemicals$$a2-fluoro-N-methyl-4-(7-(quinolin-6-yl-methyl)imidazo(1,2-b)(1,2,4)triazin-2-yl)benzamide
000130705 650_7 $$2NLM Chemicals$$aBenzamides
000130705 650_7 $$2NLM Chemicals$$aBridged Bicyclo Compounds, Heterocyclic
000130705 650_7 $$2NLM Chemicals$$aCulture Media, Conditioned
000130705 650_7 $$2NLM Chemicals$$aHGF protein, human
000130705 650_7 $$2NLM Chemicals$$aRNA, Small Interfering
000130705 650_7 $$067256-21-7$$2NLM Chemicals$$aHepatocyte Growth Factor
000130705 650_7 $$0EC 2.7.10.1$$2NLM Chemicals$$aMET protein, human
000130705 650_7 $$0EC 2.7.10.1$$2NLM Chemicals$$aProto-Oncogene Proteins c-met
000130705 7001_ $$aBashari, Muhammad Hasan$$b1
000130705 7001_ $$aFan, Feng-Juan$$b2
000130705 7001_ $$aMalvestiti, Stefano$$b3
000130705 7001_ $$aSchneeweiss, Andreas$$b4
000130705 7001_ $$aWuchter, Patrick$$b5
000130705 7001_ $$0P:(DE-He78)ed0321409c9cde20b380ae663dbcefd1$$aJäger, Dirk$$b6$$udkfz
000130705 7001_ $$0P:(DE-He78)04fd3ee9c4faa3e73a2271b1e3c37dc0$$aPodar, Klaus$$b7$$eLast author$$udkfz
000130705 773__ $$0PERI:(DE-600)2267670-3$$a10.1371/journal.pone.0150507$$gVol. 11, no. 3, p. e0150507 -$$n3$$pe0150507 -$$tPLoS one$$v11$$x1932-6203$$y2016
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