Epidermal Growth Factor (EGF) Promotes Human Malignant Glioma Invasion by Mediating Secretion of Human Cytomegalovirus Infected Monocyte-Derived Macrophages

Abstract

Human malignant glioma is the most aggressive brain tumor which lacks efficient therapies. Accumulating evidence indicates that human malignant gliomas are universally infected with human cytomegalovirus (HCMV). Recent studies demonstrate that tumor-associated macrophages (TAMs) density is associated with glioma grade. We hypothesize that virus affected the secretion of macrophages which infiltrated into glioma to promote the glioma cell invasion. Supporting this hypothesis, we showed that the secretion factor EGF had increased when HCMV infect macrophages. And the expression of the epidermal growth factor receptor (EGFR) on the surface of malignant U87 cells also up-regulated, indicating the infection of HCMV can impact the secretion factor EGF of macrophages and then activates EGFR of malignant glioma cells. We measured focal adhesion kinase FAK Tyr397 which is necessary for cell mobility. HCMV infected-macrophages can up-regulate the expression of FAK Tyr397 of malignant U87 cells. Together, these results provide evidences that EGF from infected-macrophage can activate EGFR of human malignant glioma and promote glioma cell invasion. In conclusion, these findings indicate that infected-macrophage with HCMV play an important role in the invasion of glioma and may act as a potential target to prevent its invasion.

Tumor-Associated Microglia and Macrophages in the Glioblastoma Microenvironment and Their Implications for Therapy

“…Many signaling factors released by TAMs play critical roles in glioblastoma stemness and proliferation. Epidermal growth factor (EGF) receptors (EGFRs) play crucial roles in glioma cell proliferation, and tumor-associated microglia secrete EGF that activates EGFR in glioblastoma cells [73][74][75]. In addition, stress-induced phosphoprotein 1 (STIP1) secreted by TAMs induces proliferation of glioma cells in vitro [76,77], while IL-10 was shown to promote glioma cell proliferation via JAK2/STAT3 signaling in a glioma model [78].…”