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.

Extracellular acidity strengthens mesenchymal stem cells to promote melanoma progression

“…38 Then, it was demonstrated that stromal cells may perform aerobic glycolysis under the influence of tumor cells and donate lactate to feed OxPhos metabolism of tumor cells, the so-called "Reverse Warburg Effect." [39][40][41] Metformin, a drug that is found to be effective in tumors, [42][43][44][45] when it was added in acidic medium, which will be used for MSC conditioning, blocks TGFb expression and reverts inhibition of GLUT 1 and 3 elicited by acidic medium in MSC. Moreover, melanoma cells conditioned by LpH-metformin-treated MSC medium exhibited a reconstituted epithelial-like profile and a reduced invasion, that were associated with a reduction of GLUT 1, 3.…”

2-Methoxyestradiol Reverses the Pro-Carcinogenic Effect of L-Lactate in Osteosarcoma 143B Cells

“…Interestingly, a variety of human cancer cell lines and human tumors, including breast, prostate, head, neck, and osteosarcoma cancers, import these metabolites and deliver them to the mitochondrial TCA cycle, thereby promoting ATP generation and cell proliferation (1-14). According to this 'reverse Warburg effect', tumor cells can induce metabolic reprogramming by shuttling lactate as an energy source to neighboring cancer cells, to the adjacent stroma and to vascular endothelial cells (1,14).Tumors contain both aerobic and hypoxic regions that form a metabolic symbiosis that is crucial for tumor cell survival (15, 16). The cancer cells located in the hypoxic regions export lactate, which acidifies the tumor environment; the cells located in the aerobic regions, however, import lactate and utilize it for oxidative phosphorylation (4).…”

“…It has been demonstrated that the secretion of lactate and ketones by the mesenchymal stem cells drives mitochondrial biogenesis and increases the mitochondrial activity in osteosarcoma cells (1, 483 This article is freely accessible online.…”

“…These characteristics are known as the 'Warburg effect' (1)(2)(3). The 'Warburg effect' is also observed in cancer-associated fibroblasts and mesenchymal stem cells (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11), which secrete lactate and ketones into the microenvironment of the tumor. Lactic acid exists as L-and D-optical isomers.…”

Testis peritubular myoid cells increase their motility and express matrix‐metalloproteinase 9 (MMP‐9) after interaction with embryonal carcinoma cells

“…Carcinoma in situ of the testis, CIS (Toppari, 2013) is generally considered to be the common precursor of the most frequent male germ cell tumor, i.e., a group that is classified as Type II TGCT in humans and that consists of seminoma and non-seminoma tumors (Oosterhuis & Looijenga, 2005). The important role of the cancerous reactive stroma and tumoral microenvironment has been described in the progression of a number of tumors, including breast cancer (Stuelten et al, 2010), colon carcinoma (De Wever et al, 2010a,b;De Wever et al, 2014), osteosarcoma (Bonuccelli et al, 2014), prostate cancer (Carstens et al, 2014) and testis germinal tumors (Dıez-Torre et al, 2004). Nevertheless, the precise mechanisms by which the tumor stroma affects TGCT progression still remain poorly understood.…”