In this landscape, the overexpression of the pregnancy associated plasma protein-A (PAPP-A), a metalloproteinase that cleaves IGFBP4, increases the bioavailability of IGFs on the cell surface, which acts in autocrine/paracrine manner to increase locally available ligands for IGF1R and IR-A activation in tumor cells [48,49]. This evidence concerns the gene PAPPA and neoplasm.