Abstract
Studies have shown that mesenchymal stem/stromal cells (MSCs) from bone marrow are involved in the growth and metastasis of solid tumors but the mechanism remains unclear in osteosarcoma (OS). Previous studies have raised the possibility that OS cells may receive support from associated MSCs in the nutrient deprived core of the tumors through the release of supportive macromolecules and growth factors either in vesicular or non-vesicular forms. In the present study, we used stressed mesenchymal stem cells (SD-MSCs), control MSCs and OS cells to examine the hypothesis that tumor-associated MSCs in nutrient deprived core provide pro-proliferative, anti-apoptotic, and metastatic support to nearby tumor cells. Assays to study of the effects of SD-MSC conditioned media revealed that OS cells maintained proliferation when compared to OS cells grown under serum-starved conditions alone. Furthermore, OS cells in MSCs and SD-MSC conditioned media were significantly resistant to apoptosis and an increased wound healing rate was observed in cells exposed to either conditioned media or EVs from MSCs and SD-MSCs. RT-PCR assays of OS cells incubated with extracellular vesicles (EVs) from SD-MSCs revealed microRNAs that could potentially target metabolism and metastasis associated genes as predicted by in silico algorithms, including monocarboxylate transporters, bone morphogenic receptor type 2, fibroblast growth factor 7, matrix metalloproteinase-1, and focal adhesion kinase-1. Changes in the expression levels of focal adhesion kinase, STK11 were confirmed by quantitative PCR assays. Together, these data indicate a tumor supportive role of MSCs in osteosarcoma growth that is strongly associated with the miRNA content of the EVs released from MSCs under conditions that mimic the nutrient deprived core of solid tumors.
Highlights
Osteosarcoma (OS) is the eighth most common type of cancer found in children and adolescents, accounting for approximately 20% of all primary bone cancers
The following are the different types of media used in the manuscript- Complete conditioned media (CCM): DMEM with 10% FBS and 1% Penicillin- Streptomycin; Serum deprived media (SDM): DMEM without FBS and with 1% Penicillin- Streptomycin; Conditioned media (CM): media collected from mesenchymal stem/stromal cells (MSCs) culture plates grown in SDM
The cell number of KRSOS cells grown in the presence of stressed mesenchymal stem cells (SD-MSCs) inserts was more than 3-fold higher than OS cells grown without serum, but there was only a 20% increase in the cell number of serum-deprived OS cells grown in the presence of inserts containing MSCs (Fig 1A)
Summary
Osteosarcoma (OS) is the eighth most common type of cancer found in children and adolescents, accounting for approximately 20% of all primary bone cancers. The 5-year survival rate for osteosarcoma has increased from 20% to 70% since the 1970’s. For patients with metastatic disease at initial diagnosis, survival remains at 20–30% [1]. Mutations in the retinoblastoma and p53 tumor suppressor pathways and increased expression of the protooncogenes c-fos and c-myc are found in the majority of osteosarcomas. The insulin-like growth factor, VEGF, and transforming growth factor pathways are known to be among the key signal transduction pathways involved in OS progression. Despite the similar mutations and signaling pathways recognized in the disease, OS tumors have shown a large amount of heterogeneity which has made it difficult to improve the long term survival of patients with metastasis at initial diagnosis
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