EDN1 and neoplasm: Physical factors within the bone microenvironment, namely hypoxia, acid pH and extracellular Ca2+, and bone-derived growth factors, such as transforming growth factor β (TGFβ) and insulin growth factor (IGF), activate the tumor expression of osteoblast-stimulatory factors, including bone morphogenetic proteins (BMPs), VEGF and endothelin 1 (ET-1).