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

GATTI, G; QUINTAR, A; ANDREANI, V; NICOLA, JP; MALDONADO, C; MASINI-REPISO AM; RIVERO, V; MACCIONI, M

PROSTATE

WILEY-LISS, DIV JOHN WILEY & SONS INC

Lugar: New York; Año: 2009 vol. 69 p. 1387 - 1397

0270-4137

BACKGROUND. Chronic inflammation has been postulated to be an important driving force to prostate carcinoma. Toll-like receptors (TLRs) compose a family of receptors mainly expressed on immune cells. Recently, functional TLRs have been shown to be also expressed in numerous cancer cells, but their significance has only recently begun to be explored. The purpose of this study was to investigate the putative role of TLR4 expression in prostate carcinoma.METHODS. To determine if there is an association between TLR4 expression and themalignancy of the tumor, 35 prostate carcinoma samples showing different Gleason gradeswere analyzed by immunohistochemistry. Also, to explore the functionality of the receptorsexpressed on the epithelium, we analyzed the type of cytokine response elicited and thesignaling pathways involved after TLR4 triggering in the human prostate adenocarcinoma cell line, DU-145.RESULTS. TLR4 is expressed in the normal prostate gland in both stroma and epithelium.TLR4 expression significantly drops to negative values as the Gleason grade augments inboth, stroma and epithelium. Moreover, DU-145 cells also exhibit TLR4 expression andrespond to TLR4 agonists, activating the transcription factor NF-kB and increasing theexpression of pro-inflammatory mediators. Inhibition of the molecular adaptors MyD88 andMAL by overexpression of dominant-negative mutants diminished LPS-induced activation of NF-kB, showing that DU-145 cells activate the NF-kB through MyD88-dependent signaling pathways.CONCLUSIONS. We hypothesize that TLR4 in prostate cells could synergize with innateimmune cells contributing to an eventual inflammatory process, which in genetically proneindividuals could promote carcinogenesis.