In conclusion, this study (1) adds new support to the link between the expression of EGF family growth factors and tumor sensitivity to EGFR inhibitors in the context of wild-type EGFR; (2) demonstrates that EGF family ligands are not functionally redundant during tumorigenesis but play simultaneous, specific, and discrete pathological functions inside different cellular compartments of the same tumor; and (3) describes a novel in vivo proangiogenic mechanism driven by Egfr signaling inside pericytes and mediated by mesenchyme-derived Hb-egf. This evidence concerns the gene EGF and neoplasm.