EGFRis a member of the ErbB family of tyrosine kinase receptors, transmitting a growth signal induced by EGFR ligands such as TGFαand EGF in normal and cancer cells. It is a key factor in growth, invasion, and metastasis of tumor, thus often being used as a predictive factor of poor prognosis and a principal target for therapeutic intervention. Since the majority of deaths from cancer are caused by the metastases, a sequential and selective course containing stochastic elements from both cancer cells and its microenvironment, more and more attentions has been paid on the latter. The fact that EGFR signaling creates a conducive microenvironment for cance cells metastasis, provides a rationale for inhibiting EGFR signaling in TGFα-positive cancers.
Angiogenesis plays a key role in the initiation of metastases, which supplies adequate oxygen and nutrients for tumor cell proliferation and survival. The angiogenic proteins (VEGFA and IL-8) as well as proteolytic enzymes of MMP family (MMP-2 and MMP-9) which perform several key functions during angiogenesis , are found to be strongly expressed in the microenvironment of TGFα-positive tumors. Moreover, TGFβand EGFR have recently been implicated in the process of epithelial-mesenchymal transition (EMT), which comprises a switch in cell differentiation from polarized epithelial cells to contractile and motile mesenchymal cells. It has been proved that a tyrosine kinase inhibitor of EGFR signaling in combination with conventional therapy could induce a significant decrease in proliferation of tumor cells and significant apoptosis of both tumor cells and endothelial cells. Furthermore, antineovascular therapy targeting the EGFR and VEGFR signaling in tumor vasculature may provide a new approach to the treatment of cancer.