Metastatic Progression of Prostate Cancer and E-Cadherin : Regulation by Zeb1 and Src Family Kinases
Expression of E-cadherin is used to monitor the epithelial phenotype, and its loss is suggestive of epithelialmesenchymal transition (EMT). EMT triggers tumor metastasis. Exit from EMT is marked by increased E-cadherin expression and is considered necessary for tumor growth at sites of metastasis; however, the mechanisms associated with exit from EMT are poorly understood. Herein are analyzed 185 prostate cancer metastases, with significantly higher E-cadherin expression in bone than in lymph node and soft tissue metastases. To determine the molecular mechanisms of regulation of E-cadherin expression, three stable isogenic cell lines from DU145 were derived that differ in structure, migration, and colony formation on soft agar and Matrigel. When injected into mouse tibia, the epithelial subline grows most aggressively, whereas the mesenchymal subline does not grow. In cultured cells, ZEB1 and Src family kinases decrease E-cadherin expression. In contrast, in tibial xenografts, E-cadherin RNA levels increase eight- to 10-fold despite persistent ZEB1 expression, and in all ZEB1-positive metastases (10 of 120), ZEB1 and E-cadherin proteins were co-expressed. These data suggest that transcriptional regulation of E-cadherin differs in cultured cells versus xenografts, which more faithfully reflect E-cadherin regulation in cancers in human beings. Furthermore, the aggressive nature of xenografts positive for E-cadherin and the frequency of metastases positive for E-cadherin suggest that high Ecadherin expression in metastatic prostate cancer is associated with aggressive tumor growth.
Putzke, A.P., Ventura AP, Bailey AM, Akture C, Opoku-Ansah J, Celiktas M, Hwang MS, Darling DS, Coleman IM, Nelson PS, Nguyen HM, Corey E, Tewari M, Morrissey C, Vessella RL, Knudsen BS. (2011). Metastatic progression of prostate cancer and e-cadherin regulation by zeb1 and SRC family kinases. Am J Pathol. 179(1):400-10.