Triggering of Toll-like Receptor 4 Expressed on Human Head and Neck Squamous Cell Carcinoma Promotes Tumor Development and Protects the Tumor from Immune Attack

• Published in: Cancer research (Chicago, Ill.) Ill.), 2009-04, Vol.69 (7), p.3105-3113
• Main Authors: SZCZEPANSKI, Miroslaw J, CZYSTOWSKA, Malgorzata, SZAJNIK, Marta, HARASYMCZUK, Malgorzata, BOYIADZIS, Michael, KRUK-ZAGAJEWSKA, Aleksandra, SZYFTER, Witold, ZEROMSKI, Jan, WHITESIDE, Theresa L
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic agents; Apoptosis - drug effects; Apoptosis - immunology; Biological and medical sciences; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - immunology; Carcinoma, Squamous Cell - pathology; Case-Control Studies; Cell Growth Processes - physiology; Cisplatin - pharmacology; Cytokines - biosynthesis; Cytokines - immunology; Female; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - immunology; Head and Neck Neoplasms - pathology; Humans; Lipopolysaccharides - pharmacology; Male; Medical sciences; Middle Aged; Myeloid Differentiation Factor 88 - immunology; Myeloid Differentiation Factor 88 - metabolism; NF-kappa B - immunology; NF-kappa B - metabolism; Otorhinolaryngology (head neck, general aspects and miscellaneous); Otorhinolaryngology. Stomatology; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - immunology; Phosphatidylinositol 3-Kinases - metabolism; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Signal Transduction - immunology; Toll-Like Receptor 4 - biosynthesis; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - immunology; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-08-3838

Toll-like receptors (TLR) expressed on inflammatory cells play a key role in host defense against pathogens, benefiting the host. TLR are also expressed on tumor cells. To evaluate the role of TLR in tumor cells, we investigated TLR4 signaling effects on human head and neck squamous cell carcinoma (HNSCC). Tumor tissues were obtained from 27 patients with laryngeal and 12 with oral cavity cancers. Normal mucosa was obtained from 10 patients with nonneoplastic disorders. Smears for bacteria were taken from all patients during surgery. TLR4 expression in tumors and HNSCC cell lines (PCI-1, PCI-13, and PCI-30) was detected by reverse transcription-PCR and immunohistochemistry. Cell growth, apoptosis, nuclear factor-kappaB (NF-kappaB) translocation, and MyD88 and IRAK-4 expression, as well as Akt phosphorylation were measured following tumor cell exposure to the TLR4 ligand lipopolysaccharide (LPS). Tumor cell sensitivity to NK-92-mediated lysis was evaluated in 4-hour (51)Cr-release assays. Cytokine levels in HNSCC supernatants were measured in Luminex-based assays. TLR4 was expressed in all tumors, HNSCC cell lines, and normal mucosa. The TLR4 expression intensity correlated with tumor grade. LPS binding to TLR4 on tumor cells enhanced proliferation, activated phosphatidylinositol 3-kinase/Akt pathway, up-regulated IRAK-4 expression, induced nuclear NF-kappaB translocation, and increased production (P