Role of mesenchymal stem cells in osteosarcoma and metabolic reprogramming of tumor cells

Abstract

// Gloria Bonuccelli 1 , Sofia Avnet 2 , Giulia Grisendi 3 , Manuela Salerno 1 , Donatella Granchi 2 , Massimo Dominici 3 , Katsuyuki Kusuzaki 4 , Nicola Baldini 1 , 2 1 Department of Biomedical and Neuromotion Sciences, Alma Mater Studiorum-University of Bologna, Bologna, Italy 2 Laboratory for Orthopedic Pathophysiology and Regenerative Medicine, Rizzoli Orthopedic Institute, Bologna, Italy 3 Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy 4 Department of Molecular Cell Physiology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan Correspondence to: Dr. Gloria Bonuccelli, email: gloria.bonuccelli@gmail.com Keywords: osteosarcoma, mesenchymal stem cells, lactate, MCT-1, MCT-4 Received: May 21, 2014 Accepted: July 23, 2014 Published: July 28, 2014 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.