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Neuroimmune mechanisms of behavioral alterations in a syngeneic murine model of human papilloma virus-related head and neck cancer.

ABSTRACT: Patients with cancer often experience a high symptom burden prior to the start of treatment. As disease- and treatment-related neurotoxicities appear to be additive, targeting disease-related symptoms may attenuate overall symptom burden for cancer patients and improve the tolerability of treatment. It has been hypothesized that disease-related symptoms are a consequence of tumor-induced inflammation. We tested this hypothesis using a syngeneic heterotopic murine model of human papilloma virus (HPV)-related head and neck cancer. This model has the advantage of being mildly aggressive and not causing cachexia or weight loss. We previously showed that this tumor leads to increased IL-6, IL-1?, and TNF-? expression in the liver and increased IL-1? expression in the brain. The current study confirmed these features and demonstrated that the tumor itself exhibits high inflammatory cytokine expression (e.g., IL-6, IL-1?, and TNF-?) compared to healthy tissue. While there is a clear relationship between cytokine levels and behavioral deficits in this model, the behavioral changes are surprisingly mild. Therefore, we sought to confirm the relationship between behavior and inflammation by amplifying the effect using a low dose of lipopolysaccharide (LPS, 0.1mg/kg). In tumor-bearing mice LPS induced deficits in nest building, tail suspension, and locomotor activity approximately 24h after LPS. However, these mice did not display an exacerbation of LPS-induced weight loss, anorexia, or anhedonia. Further, while heightened serum IL-6 was observed there was minimal priming of liver or brain cytokine expression. Next we sought to inhibit tumor-induced burrowing deficits by reducing inflammation using minocycline. Minocycline (?50mg/kg/day in drinking water) was able to attenuate tumor-induced inflammation and burrowing deficits. These data provide evidence in favor of an inflammatory-like mechanism for the behavioral alterations associated with tumor growth in a syngeneic murine model of HPV-related head and neck cancer. However, the inflammatory state and behavioral changes induced by this tumor clearly differ from other forms of inflammation-induced sickness behavior.

SUBMITTER: Vichaya EG

PROVIDER: S-EPMC5402618 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Neuroimmune mechanisms of behavioral alterations in a syngeneic murine model of human papilloma virus-related head and neck cancer.

Vichaya Elisabeth G EG Vermeer Daniel W DW Christian Diana L DL Molkentine Jessica M JM Mason Kathy A KA Lee John H JH Dantzer Robert R

Psychoneuroendocrinology 20170211

Patients with cancer often experience a high symptom burden prior to the start of treatment. As disease- and treatment-related neurotoxicities appear to be additive, targeting disease-related symptoms may attenuate overall symptom burden for cancer patients and improve the tolerability of treatment. It has been hypothesized that disease-related symptoms are a consequence of tumor-induced inflammation. We tested this hypothesis using a syngeneic heterotopic murine model of human papilloma virus ( ...[more]

PMID: 28259044

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Project description:Introduction: Human Papilloma Virus (HPV) is associated with a subset of head and neck squamous cell carcinoma (HNSCC), between 15% and 35% of HNSCC harboring HPV, almost exclusively of subtype 16. Demographic and exposure differences between HPV-positive (+) and negative (-) HNSCCs suggest that HPV(+) tumors may constitute a subclass with different biology, while clinical differences have also been observed. In this study, gene expression profiles of HPV(+) and (-) tumors were compared to further explore the biological effect of HPV in HNSCC. Methods: Thirty-six HNSCC tumors were analyzed for gene expression using Affymetrix Human 133U Plus 2.0 GeneChip and for HPV using consensus primers for HPV L1, E6 and E7 by PCR and RT-PCR. Results: Eight (22%) of 36 tumors were positive for HPV, all of the HPV 16 subtype, and the HPV positive samples also expressed viral HPV E6 mRNA determined by RT-PCR. Patients with HPV(+) HNSCCs were on average younger than those with HPV(-) tumors (mean age 50.2 vs. 58.7). Statistical analysis using Significance Analysis of Microarrays (SAM) based on HPV status as a supervising parameter resulted in a list of 91 genes that were differentially expressed with statistical significance. Results for a sub-set of these genes were verified by RT-PCR. Genes highly expressed in HPV(+) samples included cell cycle regulators (p16INK4A, p18 and CDK2) and transcription factors (TAF7L, RFC4, RPA2 and TFDP2). The microarray data were also investigated using DIGMap to map genes by chromosomal location. A large number of genes on chromosome 3q24-qter was found to be overrepresented in HPV(+) tumors. Conclusion: The gene expression profile associated with HPV reflects alterations in cell cycle and proliferation signals. Further investigation of differentially expressed genes may reveal the unique pathways in HPV(+) tumors that may explain the different natural history and biological properties of these tumors. These properties may be exploited as a target of novel therapeutic agents in HNSCC treatment. Experiment Overall Design: Patient selection and specimen collection. Thirty-six freshly frozen tumor samples were prospectively collected from patients undergoing surgery or biopsy for HNSCC at the University of North Carolina (UNC) at Chapel Hill (21 patients) and Vanderbilt University (15 patients). All tissues were snap-frozen in liquid nitrogen within 30 minutes of surgical resection or biopsy, and kept at -80oC until further processing. All patients consented to participation in this study under protocols approved by IRB at the two institutions. Experiment Overall Design: HPV detection and DNA sequencing. Tumor DNAs were tested for the presence of HPV DNA using a previously established PCR-based method [11]. This method employs degenerate PCR primers (MY09 and MY11, WD72/76 and WD66/67/154) that are designed to represent highly conserved HPV L1 and E6 sequences present in all major types of HPV. In addition, all HPV-positive samples were also tested with a HPV16-specific PCR for E7 (primer A: 5'-GGA CCG GTC GAT GTA TGT CT-3' and primer B: 3'-TAA AAC CAT CCA TTA CAT CCC G-5'). As a positive control for amplification, primers for beta-globin are included with each sample [11]. Optimal conditions for this combined PCR were determined using DNA from the cervical carcinoma cell line SiHa, which harbors on average 2 copies of HPV16 DNA per cell [11]. Other positive control cell lines were CaSki (HPV16) and HeLa (HPV18). For each case, 200 nanograms of tumor DNA were tested for the presence of HPV DNA. PCR samples which showed amplification products indicating the presence of HPV were purified using PCR purification columns (Qiagen, Valencia, CA) and subjected to bi-directional sequence analysis. In all of such cases, a positive identification of the HPV type could be made. Experiment Overall Design: RNA isolation and DNA microarray analysis. Each tumor was examined by H&E staining to ensure presence of tumor and enriched by macrodissection to achieve a minimum of 70% tumor cells in each preparation. Total RNA was purified from frozen tumors using Qiagen RNeasy Mini Kit according to the manufacturer's recommendations (Qiagen, Valencia, CA) using approximately 10-20 milligram of wet tissue from each sample. Fifty nanograms of the total RNA was amplified using NuGen RNA Amplification kit (NuGen, San Carlos, CA) and labeled ENZO BioArray High Yield RNA Transcript Labeling Kit (Affymetrix, Santa Clara, CA) according to the manufacturer's recommendations. Fifteen micrograms of biotin-labeled aRNA was fragmented and the quality of the RNA was reconfirmed using the Agilent RNA 6000 Nano LabChip Kit and Agilent 2100 bioanalyzer. The fragmented, biotin-labeled aRNA was combined with the hybridization mix and loaded on to the Affymetrix Human Genome U133 plus 2.0 GeneChip. After hybridization, the GeneChip was washed, stained with Strepavidin/phycoerythrin conjugate and biotinylated antibody, and scanned according to the manufacturer's recommendations. The raw microarray data was normalized using Perfect Match software for further statistical analyses.

Dataset Information

Neuroimmune mechanisms of behavioral alterations in a syngeneic murine model of human papilloma virus-related head and neck cancer.

Publications

Neuroimmune mechanisms of behavioral alterations in a syngeneic murine model of human papilloma virus-related head and neck cancer.

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