Epidermal Growth Factor (EGF)-enhanced Vascular Cell Adhesion Molecule-1 (VCAM-1) Expression Promotes Macrophage and Glioblastoma Cell Interaction and Tumor Cell Invasion

Yanhua Zheng,Weiwei Yang,Kenneth Aldape,Jie He,Zhimin Lu

doi:10.1074/jbc.m113.499020

Abstract

Activated EGF receptor (EGFR) signaling plays an instrumental role in glioblastoma (GBM) progression. However, how EGFR activation regulates the tumor microenvironment to promote GBM cell invasion remains to be clarified. Here, we demonstrate that the levels of EGFR activation in tumor cells correlated with the levels of macrophage infiltration in human GBM specimens. This was supported by our observation that EGFR activation enhanced the interaction between macrophages and GBM cells. In addition, EGF treatment induced up-regulation of vascular cell adhesion molecule-1 (VCAM-1) expression in a PKCε- and NF-κB-dependent manner. Depletion of VCAM-1 interrupted the binding of macrophages to GBM cells and inhibited EGF-induced and macrophage-promoted GBM cell invasion. These results demonstrate an instrumental role for EGF-induced up-regulation of VCAM-1 expression in EGFR activation-promoted macrophage-tumor cell interaction and tumor cell invasion and indicate that VCAM-1 is a potential molecular target for improving cancer therapy.

Highlights

The mechanism underlying EGF receptor (EGFR) activation-promoted glioblastoma (GBM) cell invasion remains elusive
Statistical analysis revealed a strong positive correlation between levels of phospho-EGFR Tyr-1172 expression and macrophage staining (r ϭ 0.59, p Ͻ 0.01) (Fig. 1B). These results suggest that EGFR activation results in macrophage infiltration into human GBM tumors
EGF Stimulation Increases Macrophage Binding to GBM Cells—To further examine the relationship between EGFR activation in tumor cells and macrophage recruitment to tumors, we examined whether EGF induces binding of GBM cells to THP-1 immortalized monocytes, which were derived from an acute monocytic leukemia patient and have been used as models to mimic the function and regulation of monocytes and macrophages [28]

Summary

Background

The mechanism underlying EGF receptor (EGFR) activation-promoted glioblastoma (GBM) cell invasion remains elusive. Results: EGFR activation resulted in PKC⑀- and NF-␬B-dependent VCAM-1 up-regulation, which subsequently promoted the interaction between macrophages and GBM cells, as well as GBM cell invasion. Conclusion: EGF-induced VCAM-1 up-regulation plays an instrumental role in EGFR activation-promoted macrophagetumor cell interaction and tumor cell invasion. We demonstrate that the levels of EGFR activation in tumor cells correlated with the levels of macrophage infiltration in human GBM specimens. Depletion of VCAM-1 interrupted the binding of macrophages to GBM cells and inhibited EGF-induced and macrophage-promoted GBM cell invasion These results demonstrate an instrumental role for EGF-induced up-regulation of VCAM-1 expression in EGFR activation-promoted macrophage-tumor cell interaction and tumor cell invasion and indicate that VCAM-1 is a potential molecular target for improving cancer therapy. Up-regulated VCAM-1 expression enhanced the interaction between macrophages and GBM cells and EGF-induced and macrophage-mediated tumor cell invasion

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION