Irradiation of primary human gliomas triggers dynamic and aggressive survival responses involving microvesicle signaling

Abstract

Malignant gliomas are heterogeneous populations of dynamically interacting cells. Genomic and transcriptional changes define this cellular hierarchy and allow certain tumor cells to co-opt metabolic machinery and adopt gene expression profiles that promote cellular reprogramming. Resultant expansion of privileged subpopulations can then rapidly adapt to microenvironmental stress that ultimately influence tumor response to therapeutic intervention. In this study, primary gliomas were subjected to acute or chronic irradiation and analyzed for changes in survival parameters, oxidative stress, gene expression, and cell invasion before and after treatment with secreted microvesicles isolated from irradiated and nonirradiated glioma cells. We found that primary gliomas exposed to ionizing radiation undergo metabolic changes that increase oxidative stress, alter gene expression, and affect the contents of and response to cellular secreted microvesicles. Radiation-induced changes were exacerbated under chronic as compared to acute irradiation paradigms and promoted cellular reprogramming through enhanced expression of key transcription factors and regulators involved in differentiation and pluripotency (SOX2, POU3F2, SALL2, OLIG2, NANOG, POU5F1v1, MSI1). Irradiation also affected changes in paracrine signaling mediated by cellular secreted microvesicles that significantly altered target cell phenotype. Primary gliomas treated with microvesicles exhibited increased radioresistance and treatment with microvesicles from chronically irradiated gliomas promoted invasion via induction of increased matrix metalloproteinase II activity. Together, our data describe a complex radiation response of primary glioma cells involving metabolic and transcriptional changes that alter radiation sensitivity and induce invasive behavior. These important changes can contribute to tumor growth and recurrence, and confound interventions designed to forestall disease progression. Environ. Mol. Mutagen. 57:405-415, 2016. © 2015 Wiley Periodicals, Inc.

The role of EGFR double minutes in modulating the response of malignant gliomas to radiotherapy

“…We then carried out a study of the radiation effect on molecular changes measured by gelatin zymography and AqRT-PCR, and on redox status by fluorescence activated cell sorting. In our previous study of radiation effects on glioma cells, we found that the extracellular level of MMP2 was upregulated by radiation [ 5 ]. Here, again we found that the high-MMP2-expressing cells of 51B had increased MMP2 1-3 weeks following both acute and chronic IR.…”

“…Significant evidence points to the intra-tumoral heterogeneity of GBM as a major confounding factor for therapy, as plasticity of the subpopulation phenotypes, driven by evolving selective pressures within the tumor microenvironment, promote treatment resistance and tumor recurrence. This is supported by much of our past work demonstrating that clinically relevant irradiation (IR) paradigms were associated with increased oxidative stress, radio-resistance, cellular reprogramming and invasive behavior, of which the latter could be mediated by radiation-induced macrovesicles [ 4 , 5 ]. Similarly, work by ourselves and others has also substantiated the importance of EGFR amplification in GBM, either as chromosomal 7 polysomy or as double minute chromosomes (DMs) [ 6 , 7 ].…”

Effect of siRNA-silencing of SALL2 gene on growth, migration and invasion of human ovarian carcinoma A2780 cells

“…In addition to the effect of SALL2 on tumour growth, we studied the effect of SALL2 on tumour migration and invasion. SALL2 interacts with other transcription factors to participate in cell reprogramming and inhibition of the migration and invasion of malignant glioma cells following ionising radiation [ 36 ]. Furthermore, SALL4 is involved in invasion of different tissues by various epithelial cancers, such as colon villous epithelial cancer and prostate cancer [ 37 ].…”

Clinical Significance of Extracellular Vesicles in Plasma from Glioblastoma Patients

“…Their cargo encompasses proteins, RNA, and lipids specific for the cell of origin (3)(4)(5). In the neoplastic setting, they induce tumor progression and infiltration, sustain neoangiogenesis, inhibit immune response, and lead to chemo/radio-resistance (3,(6)(7)(8)(9)(10)(11)(12). Interestingly, extracellular vesicles can be used as circulating biomarkers because they can be easily isolated from bloodstream, urine, cerebrospinal, ascitic, amniotic, and seminal fluid (4).…”