Expression of Toll-like receptor 4 in the prostate gland and its association with the severity of prostate cancer.

GATTI G, QUINTAR AA, ANDREANI V, NICOLA JP, MALDONADO CA, MASINI-REPISO AM, RIVERO VE, MACCIONI M.

PROSTATE

Año: 2009 vol. 15 p. 1387 - 1397

0270-4137

BACKGROUND: Chronic inflammation has been postulated to be an important drivingforce to prostate carcinoma. Toll-like receptors (TLRs) compose a family ofreceptors mainly expressed on immune cells. Recently, functional TLRs have beenshown to be also expressed in numerous cancer cells, but their significance hasonly recently begun to be explored. The purpose of this study was to investigate the putative role of TLR4 expression in prostate carcinoma. METHODS: To determineif there is an association between TLR4 expression and the malignancy of thetumor, 35 prostate carcinoma samples showing different Gleason grades wereanalyzed by immunohistochemistry. Also, to explore the functionality of thereceptors expressed on the epithelium, we analyzed the type of cytokine response elicited and the signaling pathways involved after TLR4 triggering in the humanprostate adenocarcinoma cell line, DU-145. RESULTS: TLR4 is expressed in thenormal prostate gland in both stroma and epithelium. TLR4 expressionsignificantly drops to negative values as the Gleason grade augments in both,stroma and epithelium. Moreover, DU-145 cells also exhibit TLR4 expression andrespond to TLR4 agonists, activating the transcription factor NF-kappaB andincreasing the expression of pro-inflammatory mediators. Inhibition of themolecular adaptors MyD88 and MAL by overexpression of dominant-negative mutantsdiminished LPS-induced activation of NF-kappaB, showing that DU-145 cellsactivate the NF-kappaB through MyD88-dependent signaling pathways. CONCLUSIONS:We hypothesize that TLR4 in prostate cells could synergize with innate immunecells contributing to an eventual inflammatory process, which in geneticallyprone individuals could promote carcinogenesis. Prostate 69: 1387-1397, 2009. (c)2009 Wiley-Liss, Inc.