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

• Published in: The Prostate Vol. 69; no. 13; pp. 1387 - 1397
• Main Authors: Gatti, Gerardo, Quintar, Amado A., Andreani, Virginia, Nicola, Juan P., Maldonado, Cristina A., Masini-Repiso, Ana Maria, Rivero, Virginia E., Maccioni, Mariana
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 15.09.2009; Wiley-Liss
• Subjects: Adenocarcinoma - immunology; Adenocarcinoma - pathology; Adenocarcinoma - physiopathology; Biological and medical sciences; Cell Line, Tumor; Chemokines - genetics; Cytokines - genetics; Gene Expression Regulation, Neoplastic; Gleason grade; Gynecology. Andrology. Obstetrics; Humans; inflammation; Male; Male genital diseases; Medical sciences; Nephrology. Urinary tract diseases; Prostate - pathology; Prostate - physiology; prostate cancer; Prostatic Neoplasms - immunology; Prostatic Neoplasms - pathology; Prostatic Neoplasms - physiopathology; Prostatitis - immunology; Prostatitis - pathology; Prostatitis - physiopathology; Severity of Illness Index; Signal Transduction - immunology; Toll-like receptor 4; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism; tumor immunology; Tumors; Tumors of the urinary system; Up-Regulation - immunology; Urinary tract. Prostate gland; Histological grading; Andrology; Nephrology; Urinary system disease; Toll like receptor 4; tumor immunology; Prostate disease; Gynecology; Toll-like receptor 4; Gleason grade; Inflammation; Malignant tumor; Association; Immunology; Urogenital system; Male genital diseases; Prostate cancer; Prostate; Cancer
• ISSN: 0270-4137; 1097-0045
• DOI: 10.1002/pros.20984

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‐κB 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‐κB, showing that DU‐145 cells activate the NF‐κB 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. © 2009 Wiley‐Liss, Inc.