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

Gloria Bonuccelli,Massimo Dominici,Donatella Granchi,Giulia Grisendi,Manuela Salerno,Sofia Avnet,Katsuyuki Kusuzaki,Nicola Baldini

doi:10.18632/oncotarget.2243

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.

Highlights

In addition to cancer cells, a number of reactive elements are present in the tumor microenvironment, including endothelial cells, immune cells, and fibroblastlike stromal cells, playing a key role in the establishment and progression of the tumor [1]
We investigated the interaction between mesenchymal stem cells (MSC) and OS cells and, for the first time, were able to demonstrate the induction of aerobic glycolysis in MSC as a consequence of oxidative stress induced by OS cells
These results indicate that, in the co-culture system mimicking tumor microenvironment, MSC induce mitochondrial activity and biogenesis in OS cells

Summary

Introduction

In addition to cancer cells, a number of reactive elements are present in the tumor microenvironment, including endothelial cells, immune cells, and fibroblastlike stromal cells, playing a key role in the establishment and progression of the tumor [1]. The so-called cancer-associated fibroblasts (CAF) [2, 3], that are thought to originate from mesenchymal stem cells (MSC) [4, 5], have been described as key players in tumor metabolism. According to Otto Warburg’s findings, a hallmark of cancer cells is anaerobic glycolysis even under aerobic conditions. This behavior involves increased glucose consumption with consequent excessive production of lactate and. H+, which causes a decrease of the extracellular pH to levels lower than in normal cells [6]. Most normal cells have a low rate of glycolysis followed by oxidation of pyruvate in mitochondria. The Warburg effect has important medical applications as high aerobic glycolysis has been clinically confirmed in most of malignancies

Methods

Results

Conclusion