Mesenchymal Stem/Stromal Cells under Stress Increase Osteosarcoma Migration and Apoptosis Resistance via Extracellular Vesicle Mediated Communication.
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.
Cancer Institute, University of Mississippi Medical Center, Jackson, MS, United States of America.|Department of Radiation Oncology, University of Mississippi Medical Center, Jackson, MS, United States of America.
Krishna C
KC
Vallabhaneni
Cancer Institute, University of Mississippi Medical Center, Jackson, MS, United States of America.
Meeves-Yoni
MY
Hassler
Cancer Institute, University of Mississippi Medical Center, Jackson, MS, United States of America.
Anu
A
Abraham
Cancer Institute, University of Mississippi Medical Center, Jackson, MS, United States of America.
Jason
J
Whitt
Cancer Institute, University of Mississippi Medical Center, Jackson, MS, United States of America.|Department of Pharmacology-Toxicology, University of Mississippi Medical Center, Jackson, MS, United States of America.
Yin-Yuan
YY
Mo
Cancer Institute, University of Mississippi Medical Center, Jackson, MS, United States of America.|Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS, United States of America.
Azeddine
A
Atfi
Cancer Institute, University of Mississippi Medical Center, Jackson, MS, United States of America.|Department of Biochemistry, University of Mississippi Medical Center, Jackson, MS, United States of America.
Radhika
R
Pochampally
D017209:Apoptosis; D002450:Cell Communication; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D017077:Culture Media, Conditioned; D000067128:Extracellular Vesicles / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D035683:MicroRNAs / Q000235:genetics; D012516:Osteosarcoma / Q000473:pathology*; D018384:Oxidative Stress; D059016:Tumor Microenvironment
D017077:Culture Media, Conditioned; D036341:Intercellular Signaling Peptides and Proteins; D035683:MicroRNAs