Combined targeting of interleukin‐6 and vascular endothelial growth factor potently inhibits glioma growth and invasiveness

Abstract

Interleukin‐6 (IL6) and vascular endothelial growth factor (VEGFA) are abundantly produced by glioma cells and contribute to malignancy by promoting angiogenesis, cell proliferation and resistance to apoptosis. We compared the effect of inhibiting IL6 and VEGF on U87‐derived experimental glioma grown on the chick chorio‐allantoic membrane (CAM) or in the brain of xenografted mice. Tumor growth was monitored by biomicroscopy and immunohistology. In vitro, IL6 knockdown had no effect on proliferation but substantially enhanced invasion. In the CAM experimental glioma, IL6 or VEGF knockdown reduced growth and vascularization of the tumors with a comparable efficiency, but increased invasion of residual tumor cells. In contrast, combined IL6/VEGF knockdown not only showed enhanced reduction of tumor growth and angiogenesis but also significantly prevented invasion of residual tumor cells. In mice, combining IL6 knockdown and Avastin™ treatment completely abrogated tumor development and infiltration. Molecular response of tumor cells to single or combined treatment was studied by transcriptomic profiling. Many cell cycle promoting genes and chromatin components were silenced in the double knockdown. In addition, specific migratory signatures detected in tumors under single IL6 or VEGF knockdown were partially erased in combined IL6/VEGF knockdown tumors. Our results show that treatment with a combination of IL6 and VEGF inhibitors brings synergistic antitumoral benefit and reduces global activity of major pathways of cell survival, proliferation and invasiveness in remaining tumor cells that may be induced by using VEGF or IL6 inhibitors alone. © 2009 UICC

Integrin-linked kinase regulates melanoma angiogenesis by activating NF-κB/interleukin-6 signaling pathway

“…Although previous studies have confirmed that IL-6 is important in both physiological and pathological angiogenesis (Cohen et al, 1996;Mahnke et al, 2000), IL-6 has recently received more attention as a critical cytokine implicated in the angiogenesis of several human cancers, including cervical cancer, basal cell carcinoma, glioma, gastric carcinoma and mesothelioma (Wei et al, 2003;Huang et al, 2004;Jee et al, 2004;Loeffler et al, 2005;Adachi et al, 2006;Saidi et al, 2009). Strikingly, these investigations provide evidence that IL-6 may promote VEGF-induced tumor angiogenesis.…”

“…IL-6 is known to regulate VEGF through STAT3 pathway in many cancers and thereby promotes angiogenesis (Wei et al, 2003;Huang et al, 2004;Jee et al, 2004;Saidi et al, 2009). We further examined whether silencing of IL-6 or its downstream target STAT3 in vector or ILK-overexpressing cells could affect VEGF expression.…”

Extracellular ATP reduces tumor sphere growth and cancer stem cell population in glioblastoma cells

“…As already pointed out by Shen et al [23], glioma cell lines grown on serum-containing medium for several years must be able to maintain a CSC population under this condition in order to remain tumorigenic, as is the case of U87. U87 cells grown on serum-containing medium are able to form tumors when injected into the brain of nude mice, indicating that under these conditions, the main feature of CSCs, which is the formation of tumor, is maintained [2,26,27]. Activation of P2Y receptors was shown to be mitogenic for mice neural progenitor cells, but had no effect on cell differentiation.…”

IL-1β potently stabilizes IL-6 mRNA in human astrocytes

“…For instance, IL-6 has been demonstrated to play an important role in the development and malignant progression of brain glioma by promoting angiogenesis, cell proliferation and resistance to apoptosis and radiation [3][4][5]. Moreover, a positive correlation between IL-6 gene expression and shortened survival in glioblastoma patients has been shown [6].…”