title: Role of the EGFR ligand/receptor system in the secretion of angiogenic factors in mesenchymal stem cells.
abstract: Increasing evidence suggests that bone marrow-derived mesenchymal stem cells (MSCs) are recruited into the stroma of developing tumors where they contribute to cancer progression. MSCs produce different growth factors that sustain tumor-associated neo-angiogenesis. Since the majority of carcinomas secrete ligands of the epidermal growth factor receptor (EGFR), we assessed the role of EGFR signaling in regulating the release of angiogenic factors in MSCs. Treatment of human primary MSCs and of the human osteoblastic cell line hFOB with transforming growth factor α (TGF-α), one of the main ligands of the EGFR, significantly induced activation of this receptor and of different intracellular signaling proteins, including the PI3K/AKT and the MEK/MAPK pathways. TGF-α induced a significant increase in the levels of secretion of vascular endothelial growth factor in both MSCs and hFOB. Conditioned medium from TGF-α treated MSCs showed an higher in vivo angiogenic effect as compared with medium from untreated cells. Treatment of MSCs with TGF-α also produced a significant increase in the secretion of other angiogenic growth factors such as angiopoietin-2, granulocyte-colony stimulating factor, hepatocyte growth factor, interleukin (IL)-6, IL-8, and platelet-derived growth factor-BB. Using selective MEK and PI3K inhibitors, we found that both MEK/MAPK and the PI3K/AKT signaling pathways mediate the ability of TGF-α to induce secretion of angiogenic factors in MSCs. Finally, stimulation with TGF-α increased the ability of MSCs to induce migration of MCF-7 breast cancer cells. These data suggest that EGFR signaling regulates the ability of MSCs to sustain cancer progression through the release of growth factors that promote neo-angiogenesis and tumor cell migration.
authors.affiliation: Cell Biology and Biotherapy Unit, INT-Fondazione Pascale, Naples, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: De Luca
authors.forename: Marianna
authors.initials: M
authors.lastname: Gallo
authors.forename: Donatella
authors.initials: D
authors.lastname: Aldinucci
authors.forename: Domenico
authors.initials: D
authors.lastname: Ribatti
authors.forename: Luana
authors.initials: L
authors.lastname: Lamura
authors.forename: Amelia
authors.initials: A
authors.lastname: D'Alessio
authors.forename: Rosaria
authors.initials: R
authors.lastname: De Filippi
authors.forename: Antonio
authors.initials: A
authors.lastname: Pinto
authors.forename: Nicola
authors.initials: N
authors.lastname: Normanno
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism; D042501:Angiogenic Proteins / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006801:Humans; D008024:Ligands; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016211:Transforming Growth Factor alpha / Q000494:pharmacology
chemical_list: D042501:Angiogenic Proteins; D008024:Ligands; D047428:Protein Kinase Inhibitors; D016211:Transforming Growth Factor alpha; D066246:ErbB Receptors