interleukin-8 and Oropharyngeal-Neoplasms

Cytokines and growth factors modulated by transcription factor nuclear factor-kappaB and secreted by tumor and stromal cells are detectable in serum of patients with advanced cancers, including head and neck squamous cell carcinomas (SCC). Longitudinal changes in these serum factors could be early biomarkers of treatment response and survival.. Interleukin (IL)-6, IL-8, growth-related oncogene-1 (GRO-1), vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF) concentrations were determined by Luminex multiplex assay using serum obtained at baseline and every 3 months in a prospective study of 30 patients with locally advanced (stage III/IV) oropharyngeal SCC receiving chemoradiation therapy. The relationship between baseline and direction of change in individual and multiple cytokines with cause-specific and disease-free survival was determined by Cox proportional hazards models and Kaplan-Meier survival analysis. Statistical analyses included adjustment for smoking status and response to chemoradiation.. Three-year cause-specific and disease-free survival was 74.4% and 68.9%. Nonsmoking history (P = 0.05) and higher baseline VEGF (P = 0.003) correlated with increased survival. Longitudinal increases in levels of individual factors predicted decreased cause-specific survival when adjusted for smoking history [IL-6: relative risk (RR), 3.8; 95% confidence interval (95% CI), 2.0-7.4; P = 0.004; IL-8: RR, 1.6; 95% CI, 1.2-2.2; P = 0.05; VEGF: RR, 3.0; 95% CI, 1.6-5.6; P = 0.01; HGF: RR, 2.9; 95% CI, 1.9-4.4; P = 0.02; and GRO-1: RR, 1.2; 95% CI, 1.1-1.3; P = 0.02]. For a given individual, large increases in the upper quartile for any three or more factors predicted poorer cause-specific survival compared with patients with two or fewer large increases in factor levels (P = 0.004).. Pretreatment VEGF levels and longitudinal change in IL-6, IL-8, VEGF, HGF, and GRO-1 may be useful as biomarkers for response and survival in patients with locally advanced oropharyngeal and head and neck SCC treated with chemoradiation.

Topics: Adult; Aged; Biomarkers, Tumor; Carcinoma; Female; Gene Expression Regulation, Neoplastic; Hepatocyte Growth Factor; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; NF-kappa B; Oropharyngeal Neoplasms; Treatment Outcome; Vascular Endothelial Growth Factor A

Since morbidity and mortality rates due to oral cavity and oropharyngeal squamous cell carcinoma (OSCC) have improved little in the past 30 years, early detection or prevention of this disease is likely to be most effective. Using laser-capture microdissection, we have identified the expression of 2 cellular genes that are uniquely associated with OSCC: interleukin (IL) 6 and IL-8. These cytokines may contribute to the pathogenesis of this disease, and have been linked with increased tumor growth and metastasis.. To investigate whether IL-6 and/or IL-8 could serve as informative biomarkers for OSCC in saliva and/or serum and to determine if there is a role for saliva as a diagnostic medium for OSCC.. Patients with newly diagnosed T1 or T2 oral cavity or oropharyngeal histologically confirmed squamous cell carcinoma were recruited for the study. Age and sex-matched disease-free subjects were used as controls. Using quantitative real-time polymerase chain reaction analysis and enzyme-linked immunosorbent assay, we respectively assessed the expression of IL-6 and IL-8 in serum (controls, n = 32; patients with OSCC, n = 19) and saliva (controls, n = 32; patients with OSCC, n = 32) at the messenger RNA (mRNA) and protein levels.. Specificity and sensitivity of these biomarkers for OSCC and their predictive value.. Interleukin 8 was detected at higher concentrations in saliva (P<.01) and IL-6 was detected at higher concentrations in serum of patients with OSCC (P<.01). We confirmed these results at both the mRNA and the protein levels, and the results were concordant. The concentration of IL-8 in saliva and IL-6 in serum did not appear to be associated with sex, age, or alcohol or tobacco use (P>.75). Using statistical analysis, we were able to determine the threshold value, sensitivity, and specificity of each biomarker, as well as a combination of biomarkers, for detecting OSCC.. Our findings indicate that IL-8 in saliva and IL-6 in serum hold promise as biomarkers for OSCC. A saliva-based test could be a cost-effective adjunctive tool in the diagnosis and follow-up of patients with OSCC.

Topics: Adult; Biomarkers, Tumor; California; Carcinoma, Squamous Cell; Female; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Mouth; Mouth Neoplasms; Oropharyngeal Neoplasms; Predictive Value of Tests; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Saliva; Sensitivity and Specificity

High levels of prostaglandins are produced in human oropharyngeal carcinoma (OPC). Five human OPC cell lines tested expressed both isoforms of cyclooxygenases (COX). The pan-COX inhibitor ketorolac continuously and significantly decreased PGE(2) production and IL-6 and IL-8 levels in all OPC cell lines tested, but did not affect IL-1alpha, GM-CSF levels, or in vitro tumor cell growth. In contrast, ketorolac reduced OPC growth in vivo. The OPC cell lines used express the IL-6 receptor, and IL-6 stimulation of these cells causes transduction to occur via STAT3 pathway activation. Coincubation with OPC cell lines with conditioned medium from a TPA-exposed HL-60 cells stimulated growth proportional to the IL-6 levels measured in the conditioned medium. This growth effect was specifically inhibited by anti-IL-6 antibody. These results are consistent with cytokine products of inflammatory cells having paracrine growth effects on OPC. If chronic inflammation plays a role in promoting the development of OPC, this mechanism may also apply to other epithelial tumor systems modulated by COX activity.

Topics: Animals; Antibodies; Arachidonic Acid; Cell Division; Clinical Trials, Phase II as Topic; Culture Media, Conditioned; Cyclooxygenase Inhibitors; Dinoprostone; DNA-Binding Proteins; Granulocyte-Macrophage Colony-Stimulating Factor; HL-60 Cells; Humans; Inflammation; Interleukin-1; Interleukin-6; Interleukin-8; Isoenzymes; Ketorolac; Mice; Mice, Inbred BALB C; Models, Biological; Oropharyngeal Neoplasms; Paracrine Communication; Prostaglandin-Endoperoxide Synthases; Receptors, Interleukin-6; RNA, Messenger; Signal Transduction; STAT3 Transcription Factor; Tetradecanoylphorbol Acetate; Trans-Activators; Tumor Cells, Cultured