Leptin acts on mesenchymal stem cells to promote chemoresistance in osteosarcoma cells.

Helin Feng,Lili Zhao,Qianqian Zhang,Yi Zhao,Baoen Shan

doi:10.18632/aging.103027

Abstract

Leptin signaling influences osteoblastogenesis and modulates the fate of mesenchymal stem cells (MSCs) during bone and cartilage regeneration. Although MSCs abound in the osteosarcoma (OS) microenvironment, and leptin exhibits pro-tumorigenic properties, leptin’s influence on OS progression and chemoresistant signaling in MSCs remains unclear. Using cell viability and apoptosis assays, we showed that medium conditioned by leptin-treated human MSCs promotes cisplatin resistance in cultured human OS cells. Moreover, GFP-LC3 expression and chloroquine treatment experiments showed that this effect is mediated by stimulation of autophagy in OS cells. TGF-β expression in MSCs was upregulated by leptin and suppressed by leptin receptor knockdown. Silencing TGF-β in MSCs also abolished OS cell chemoresistance induced by leptin-conditioned medium. Cisplatin resistance was also induced when leptin-conditioned MSCs were co-injected with MG-63 OS cells to generate subcutaneous xenografts in nude mice. Finally, we observed a significant correlation between autophagy-associated gene expression in OS clinical samples and patient prognosis. We conclude that leptin upregulates TGF-β in MSCs, which promotes autophagy-mediated chemoresistance in OS cells.

Highlights

Osteosarcoma (OS) is the most common primary malignant bone neoplasm in children and adolescents [1]
To test the hypothesis that leptin acts on Mesenchymal stem cells (MSCs) to promote chemoresistance in OS, cultured human MSCs were treated with leptin (20 ng/ml) for 12 h, incubated in leptin- and serum-free Dulbecco’s modified Eagle’s medium (DMEM) for another 24 h, and the resulting conditioned media (CM) was added to cultured human OS cells (MG-63 and U-2 OS) in the presence or absence of cisplatin (0, 10, 20, or 40 μM)
After multiple intratumoral cisplatin injections, growth was unaffected only in tumors containing MG-63 cells plus leptin-treated MSCs (Figure 1E and 1F). These results indicated that leptin exposure promotes MSC-mediated chemoresistance in OS cells both in vitro and in vivo

Summary

Introduction

Osteosarcoma (OS) is the most common primary malignant bone neoplasm in children and adolescents [1]. Most cases are high-grade, and despite recent advances in therapeutic strategies combining chemotherapy, surgery, and sometimes radiotherapy, development of chemoresistance still compromises prognosis [2, 3]. MSCs are primarily found in the bone marrow but can be derived from several other tissues. MSCs can migrate to tumor sites, interact with tumor cells, and become important constituents of the tumor microenvironment [7, 8]. There is substantial research supporting a role for MSCs in the growth, migration, and chemoresistance of OS cells [9,10,11,12]. Strong evidence suggests that OS cells may originate from undifferentiated MSCs [13]

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