Osteoblasts are stimulated by metastatic tumor cell-derived factors, including FGFs, urokinase-type plasminogen activator (uPA), endothelin-1 (ET-1), prostate-specific antigen (PSA), IGFs, bone morphogenic proteins (BMPs), and VEGF.176–180 ET-1 plays a vital role in the osteoblastic response to cancer bone metastasis.181 The binding of ET-1 to the endothelin A receptor (ETAR) downregulates the autocrine production of a Wnt antagonist, Dickkopf-1 (Dkk-1).182,183 The subsequent Wnt pathway activation is crucial for the differentiation and function of osteoblasts. This evidence concerns the gene KLK3 and cancer.