Molecular signature of epithelial-mesenchymal transition (EMT) in human prostate cancer bone metastasis

Prostate cancer (PCa) has a predilection to metastasize to bone. Before metastasis can occur there is transition of the sessile epithelial cancer cells to become motile and invasive mesenchymal phenotypes by an important albeit transient process called Epithelial-to-Mesenchymal Transition (EMT). The cascade of molecular events triggered by this process is clinically relevant as they are associated with cancer stem-like cells (CSC), decreased senescence and eventual drug resistance phenotype. We interrogated some EMT markers that have been implicated in primary and bone metastasis of PCa using archived patient samples. Using an immunohistochemical approach, E-cadherin, Vimentin, ZEB1, Notch-1, PDGF-D and NF-κB were analyzed. Cases were microscopically scored using intensity (0, +1, +2, +3) and percentage of positive cells. Data was statistically analyzed using Fisher's Exact Test. Aberrant expression of EMT markers E-cadherin, Vimentin, PDGF-D, NF-κB, Notch-1 and ZEB1 was observed in PCa (primary tumor specimen) and bone metastasis tissues. The aberrant expression pattern varied according to the location within the tumor with higher expression was observed more at the invasive tumor front (ITF) vs. the center of the tumor. Notch-1 was significantly over-expressed in bone metastasis compared to primary PCa (p=0.057). The expression levels, intensity and % of positive cells of the remaining markers were not statistically significant in PCa vs. bone metastasis. In conclusion, protein expression analysis revealed the existence of EMT phenotype in the PCa and bone metastasis. Variation in the aberrant expression patterns at the invasive tumor front indicates the role of EMT markers in tumor invasion. Our results suggest that Notch-1 could play a role in PCa bone metastasis. Studies in larger patient cohorts are warranted before these EMT molecular markers can be translated to the clinical use.