EGFR signaling in invasion, angiogenesis and metastasis

Tumour invasion and metastasis are the hallmarks of advanced stage cancer and are associated with poor patient prognosis. EGFR is overexpressed in a variety of tumour types and this frequently correlates with a more aggressive tumour phenotype. In this chapter, we discuss the cellular and molecular mechanisms by which EGFR contributes to tumour progression and present evidence from experimental and clinical observations that reinforce the notion that EGFR actively contributes to the onset of metastatic disease. EGFR plays a key role in the regulation of processes central to tumour invasion including cell adhesion and motility through its interactions with molecules such as integrins, cadherins, phospholipase Cγ1 and phosphoinositide 3-kinase. In addition, EGFR signaling can contribute to both proteolysis and angiogenesis through up-regulated expression of matrix metalloproteinases (MMPs) and angiogenic cytokines e.g. VEGF-A and IL-8. The significance of these contributions to tumour invasion and metastasis is highlighted by the fact that a mutant, constitutively active receptor (EGFRvIII) associated with human cancers can induce these behaviours when transfected into fibroblasts. Finally, we discuss the use of EGFR antagonists to stem metastatic disease and their potential, in combination with additional novel agents, to improve treatment for cancer patients