Ionizing radiation and glioblastoma exosomes: implications in tumor biology and cell migration.
Exosomes are nanometer-sized lipid vesicles released ubiquitously by cells, which have been shown to have a normal physiological role, as well as influence the tumor microenvironment and aid metastasis. Recent studies highlight the ability of exosomes to convey tumor-suppressive and oncogenic mRNAs, microRNAs, and proteins to a receiving cell, subsequently activating downstream signaling pathways and influencing cellular phenotype. Here, we show that radiation increases the abundance of exosomes released by glioblastoma cells and normal astrocytes. Exosomes derived from irradiated cells enhanced the migration of recipient cells, and their molecular profiling revealed an abundance of molecules related to signaling pathways important for cell migration. In particular, connective tissue growth factor (CTGF) mRNA and insulin-like growth factor binding protein 2 (IGFBP2) protein levels were elevated, and coculture of nonirradiated cells with exosomes isolated from irradiated cells increased CTGF protein expression in the recipient cells. Additionally, these exosomes enhanced the activation of neurotrophic tyrosine kinase receptor type 1 (TrkA), focal adhesion kinase, Paxillin, and proto-oncogene tyrosine-protein kinase Src (Src) in recipient cells, molecules involved in cell migration. Collectively, our data suggest that radiation influences exosome abundance, specifically alters their molecular composition, and on uptake, promotes a migratory phenotype.
Radiation Oncology Branch, National Cancer Institute, Bethesda, MD ; University of Vermont College of Medicine, Burlington, VT ; Howard Hughes Medical Institute-National Institutes of Health Research Scholars Program, Bethesda, MD.
W Tris
WT
Arscott
Radiation Oncology Branch, National Cancer Institute, Bethesda, MD.
Anita T
AT
Tandle
Radiation Oncology Branch, National Cancer Institute, Bethesda, MD.
Shuping
S
Zhao
Radiation Oncology Branch, National Cancer Institute, Bethesda, MD ; Howard Hughes Medical Institute-National Institutes of Health Research Scholars Program, Bethesda, MD ; Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA.
Jacob E
JE
Shabason
Radiation Oncology Branch, National Cancer Institute, Bethesda, MD.
Ira K
IK
Gordon
Radiation Oncology Branch, National Cancer Institute, Bethesda, MD.
Cody D
CD
Schlaff
Biomedical Engineering and Physical Science Shared Resource, National Institute of Biomedical Imaging and Bioengineering, Bethesda, MD.
Guofeng
G
Zhang
Radiation Oncology Branch, National Cancer Institute, Bethesda, MD.
Philip J
PJ
Tofilon
Radiation Oncology Branch, National Cancer Institute, Bethesda, MD.
Kevin A
KA
Camphausen