EGFR and EGFRvIII Promote Angiogenesis and Cell Invasion in Glioblastoma: Combination Therapies for an Effective Treatment

Abstract

Epidermal growth factor receptor (EGFR) and the mutant EGFRvIII are major focal points in current concepts of targeted cancer therapy for glioblastoma multiforme (GBM), the most malignant primary brain tumor. The receptors participate in the key processes of tumor cell invasion and tumor-related angiogenesis and their upregulation correlates with the poor prognosis of glioma patients. Glioma cell invasion and increased angiogenesis share mechanisms of the degradation of the extracellular matrix (ECM) through upregulation of ECM-degrading proteases as well as the activation of aberrant signaling pathways. This review describes the role of EGFR and EGFRvIII in those mechanisms which might offer new combined therapeutic approaches targeting EGFR or EGFRvIII together with drug treatments against proteases of the ECM or downstream signaling to increase the inhibitory effects of mono-therapies.

Keywords: EGFR; EGFRvIII; angiogenesis; glioblastoma multiforme; invasion.

Figure 1

EGFR and EGFRvIII contribute to the upregulation of the extracellular matrix (ECM)-degrading proteases matrix metalloproteases (MMPs), urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (tPA), and cathepsin B, which leads to degradation of basal membrane components like collagen, laminin, and fibronectin, and facilitate the invasion of tumor cells into the surrounding tissue and blood vessels.

Figure 2

Schematic of signaling pathways activated by EGFR and EGFRvIII and their interaction with integrin and Wnt signaling. Activation upregulates different transcription factors involved in tumor cell proliferation, invasion, and angiogenesis, which can be blocked by various EGFR- and EGFRvIII-specific agents.