IGFBP7 as Key Driver of Malignancy in EGFRvIII-Positive Glioblastoma

Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Although EGFR amplification and the EGFRvIII mutation are frequent in GBM, the role of IGFBP7 and its association with EGFRvIII remain poorly understood. Here, we investigated the functional significance of IGFBP7 in GBM. IGFBP7 expression varied across human glioblastoma cell lines, with EGFRvIII-expressing cells showing particularly high levels. IGFBP7 overexpression increased proliferation, migration, and invasion, whereas IGFBP7 knockdown suppressed these malignant phenotypes. Pharmacologic inhibition revealed that blockade of the PI3K/AKT pathway more effectively reduced IGFBP7-driven proliferation and migration than MEK/ERK inhibition, indicating that PI3K/AKT is the predominant downstream mediator. IGFBP7 also elevated MMP2 and MMP9 expression, and inhibition of these proteases reduced IGFBP7 levels, suggesting a positive feedback loop that enhances invasiveness. In addition, IGFBP7 overexpression promoted tumorsphere formation and upregulated glioma stem cell markers, supporting a role in maintaining stem-associated traits. IGFBP7 further increased resistance to chemotherapeutic agents, contributing to overall tumor aggressiveness. Collectively, these findings identify IGFBP7 as a key regulator of GBM malignancy and highlight its potential as a biomarker and therapeutic target, particularly in EGFRvIII-positive glioblastoma.