Pre-Osteoblasts Stimulate Migration of Breast Cancer Cells via the HGF/MET Pathway

Abstract

IntroductionThe 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.Methods and ResultsPre-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.ConclusionsOur 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.

The Endosteal Niche in Breast Cancer Bone Metastasis

“…A 12% increase in cell migration was observed when MDA-MB-231 breast cancer cells were allowed to migrate toward medium conditioned by osteoblasts compared to control medium using the transwell migration assay (34). Using the wound healing assay, pre-osteoblasts (ALP low , OPN low , Runx2 high , Osx high , CD166 high ) but not mature osteoblasts were shown to enhance the migration of MDA-MB-231 breast cancer cells (39). By using a vybrant cell adhesion kit the authors were also able to show that adhesion of MDA-MB-231 breast cancer cells to pre-osteoblastic cells was strongly increased when compared to undifferentiated cells or mature osteoblasts, suggesting that osteoblasts regulate early stages involved in metastatic breast cancer growth (39).…”

“…Using the wound healing assay, pre-osteoblasts (ALP low , OPN low , Runx2 high , Osx high , CD166 high ) but not mature osteoblasts were shown to enhance the migration of MDA-MB-231 breast cancer cells (39). By using a vybrant cell adhesion kit the authors were also able to show that adhesion of MDA-MB-231 breast cancer cells to pre-osteoblastic cells was strongly increased when compared to undifferentiated cells or mature osteoblasts, suggesting that osteoblasts regulate early stages involved in metastatic breast cancer growth (39). Vice versa, data also suggest that breast cancer cells can stimulate the migration of mesenchymal cells, progenitors of osteoblasts (40).…”

“…One important component of the (bone) tumor microenvironment includes mesenchymal-derived cells including osteoblasts and fibroblasts or so called "endosteal niche cells." Endosteal niche cells and in particular osteoblasts are increasingly appreciated as important components of the metastatic niche (8,34,35,38,39,80,81). However, their role in supporting tumor cell homing, dormancy and disease progression remains poorly defined.…”

The N-Hexane Fraction of Myrmecodia Pendans Inhibits Cell Survival and Proliferation in Colon Cancer Cell Line

“…The cytotoxic effect of extract or fraction of Sarang Semut was evaluated in colon cancer cells using MTT assay, modified from our previous study [14][15]. Briefly, cells were seeded on 96-well plate then treated with indicated concentrations on the next day followed by incubation for 72 h in an incubator with 5% CO2 at the temperature of 37 °C.…”

Dendrimer-Trastuzumab Contrast Agent Improves Imaging of Magnetic Resonance Imaging (MRI) On Her2 Positive Breast Cancer Cell Line HCC-1954 in Apple Scaffold

“…The cytotoxic effect of Gd-DOTA-Dendrimer-Trastuzumab as well as Gd-DOTA contrast ware evaluated in breast cancer cells using MTT assay, modified from our previous study [20,21]. Briefly, cells were seeded on 96-well plate then treated with indicated concentrations on the next day followed by incubation for 72 hours in an incubator with 5% CO 2 at the temperature of 37°C.…”