Interleukin-1-induced changes in the glioblastoma secretome suggest its role in tumor progression

Abstract

The tumor microenvironment including glial cells and their inflammatory products regulates brain tumor development and progression. We have previously established that human glioma cells are exquisitely sensitive to IL-1 stimulation leading us to undertake a comparative analysis of the secretome of unstimulated and cytokine (IL-1)-stimulated glioblastoma cells. We performed label-free quantitative proteomic analysis and detected 190 proteins which included cytokines, chemokines, growth factors, proteases, cell adhesion molecules, extracellular matrix (ECM) and related proteins. Measuring area under the curve (AUC) of peptides for quantitation, the IL-1-induced secretome contained 13 upregulated and 5 downregulated extracellular proteins (p<0.05) compared to controls. Of these, IL-8, CCL2, TNC, Gal-1 and PTX3 were validated as upregulated and SERPINE1, STC2, CTGF and COL4A2 were validated as downregulated factors by immunochemical methods. A major representation of the ECM and related proteins in the glioblastoma secretome and their modulation by IL-1 suggested that IL-1 induces its effect in part by altering TGFβ expression, activity and signaling. These findings enhance our understanding of IL-1-induced modulation of glioma microenvironment, with implications for increased tumor invasion, migration and angiogenesis. They further provide novel targets for the glioblastoma intervention.

Radiotherapy induces an immediate inflammatory reaction in malignant glioma: a clinical microdialysis study

“…The gradient of cytokines in our analysis definitely point at an intratumoral source of cytokine release although the BAT area also contributes. Secretomic data from cultured tumor and astrocytic cells clearly indicates that these are capable of producing various cytokines including those highlighted in the present study [33, 34]. Nevertheless accumulated data and our immunohistochemistry results strongly imply that the overwhelming source of secreted inflammatory cytokines emanate from myeloid cell, either infiltrating macrophages or resident microglia and that myeloid cells are the drivers of other early features of reaction as astrocyte gliosis [5, 35, 36].…”

Inflammatory cytokines, interleukin-1 beta and tumor necrosis factor-alpha, upregulated in glioblastoma multiforme, raise the levels of CRYAB in exosomes secreted by U373 glioma cells

“…Although some studies on GBM secretome[26,27,28,29] (which includes shedded microvesicles, apoptotic bodies and other secretory vesicles) have been previously reported, our study focuses solely on the effects of proinflammatory cytokines on the protein cargo of discrete secretory vesicles - exosomes. Exosomes differ from other secretory vesicles in that they are endosomal in origin and result due to release of ILVs into extracellular milieu by fusion of MVBs with the plasma membrane[30,31].…”

Aberrant Expression of Interleukin-1β and Inflammasome Activation in Human Malignant Gliomas

“…miR-155 targets suppressor of cytokine signaling (SOCS) proteins potentially leading to overactive Stat3, a transcription factor important in glioma progression [31]–[34]. Our recent GBM secretome study also revealed that IL-1 upregulates secretory molecules implicated in glioma progression such as MMP2, tenascin-C, galectin-1, pentraxin 3, IL-8 and MCP-1, while (down)modulating numerous extracellular matrix (ECM) and ECM-modulating proteins [14]. These results together suggest that IL-1 controls crucial aspects of glioma signaling and progression.…”