title: Role of mesenchymal stem cells in osteosarcoma and metabolic reprogramming of tumor cells.
abstract: The tumor microenvironment plays an important role in cancer progression. Here, we focused on the role of reactive mesenchymal stem cells (MSC) in osteosarcoma (OS), and used human adipose MSC and a panel of OS cell lines (Saos-2, HOS, and 143B) to investigate the mutual effect of normal-cancer cell metabolic programming. Our results showed that MSC are driven by oxidative stress induced by OS cells to undergo Warburg metabolism, with increased lactate production. Therefore, we analyzed the expression of lactate monocarboxylate transporters. By real time PCR and immunofluorescence, in MSC we detected the expression of MCT-4, the transporter for lactate efflux, whereas MCT-1, responsible for lactate uptake, was expressed in OS cells. In agreement, silencing of MCT-1 by siRNA significantly affected the ATP production in OS cancer cells. Thus, cancer cells directly increase their mitochondrial biogenesis using this energy-rich metabolite that is abundantly provided by MSC as an effect of the altered microenvironmental conditions induced by OS cells. We also showed that lactate produced by MSC promotes the migratory ability of OS cells. These data provide novel information to be exploited for cancer therapies targeting the mutual metabolic reprogramming of cancer cells and their stroma.
authors.affiliation: Department of Biomedical and Neuromotion Sciences, Alma Mater Studiorum-University of Bologna, Bologna, Italy.
authors.forename: Gloria
authors.initials: G
authors.lastname: Bonuccelli
authors.affiliation: Laboratory for Orthopedic Pathophysiology and Regenerative Medicine, Rizzoli Orthopedic Institute, Bologna, Italy.
authors.forename: Sofia
authors.initials: S
authors.lastname: Avnet
authors.affiliation: Department of Medical and Surgical Sciences for Children and Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Grisendi
authors.affiliation: Department of Biomedical and Neuromotion Sciences, Alma Mater Studiorum-University of Bologna, Bologna, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Salerno
authors.affiliation: Laboratory for Orthopedic Pathophysiology and Regenerative Medicine, Rizzoli Orthopedic Institute, Bologna, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Granchi
authors.affiliation: Department of Medical and Surgical Sciences for Children and Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Dominici
authors.affiliation: Department of Molecular Cell Physiology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kusuzaki
authors.affiliation: Department of Biomedical and Neuromotion Sciences, Alma Mater Studiorum-University of Bologna, Bologna, Italy. Laboratory for Orthopedic Pathophysiology and Regenerative Medicine, Rizzoli Orthopedic Institute, Bologna, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Baldini
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D005455:Fluorescent Antibody Technique; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D012516:Osteosarcoma / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D059016:Tumor Microenvironment / Q000502:physiology*