Expression of Toll-like receptor 4 in the prostate gland and its association with the severity of prostate cancer.
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 the malignancy of the tumor, 35 prostate carcinoma samples showing different Gleason grades were analyzed by immunohistochemistry. Also, to explore the functionality of the receptors expressed on the epithelium, we analyzed the type of cytokine response elicited and the signaling 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 in both, stroma and epithelium. Moreover, DU-145 cells also exhibit TLR4 expression and respond to TLR4 agonists, activating the transcription factor NF-kappaB and increasing the expression of pro-inflammatory mediators. Inhibition of the molecular adaptors MyD88 and MAL by overexpression of dominant-negative mutants diminished LPS-induced activation of NF-kappaB, showing that DU-145 cells activate the NF-kappaB through MyD88-dependent signaling pathways.


CONCLUSIONS
We hypothesize that TLR4 in prostate cells could synergize with innate immune cells contributing to an eventual inflammatory process, which in genetically prone individuals could promote carcinogenesis. Prostate 69: 1387-1397, 2009. (c) 2009 Wiley-Liss, Inc.
Gatti
Gerardo
G
Facultad de Ciencias Químicas, Departamento de Bioquímica Clínica, Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI-CONICET), Córdoba, Argentina.
Quintar
Amado A
AA
Andreani
Virginia
V
Nicola
Juan P
JP
Maldonado
Cristina A
CA
Masini-Repiso
Ana Maria
AM
Rivero
Virginia E
VE
Maccioni
Mariana
M
D000230:Adenocarcinoma / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D045744:Cell Line, Tumor; D018925:Chemokines / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D011467:Prostate / Q000473:pathology / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D011472:Prostatitis / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation / Q000276:immunology
D018925:Chemokines; D016207:Cytokines; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4