EGF and neoplasm: When the tumor size becomes more than 1–2 mm3, the central tumor cells are subjected to a hypoxic microenvironment; this induces the activation of the hypoxia-inducible factor (HIF) to facilitate its binding to the hypoxia-response element (HRE) to induce cell proliferation and expression of angiogenesis factors such as epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF).