Neuroimmune mechanisms of behavioral alterations in a syngeneic murine model of human papilloma virus-related head and neck cancer - PubMed (original) (raw)
Neuroimmune mechanisms of behavioral alterations in a syngeneic murine model of human papilloma virus-related head and neck cancer
Elisabeth G Vichaya et al. Psychoneuroendocrinology. 2017 May.
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-1β, and TNF-α expression in the liver and increased IL-1β 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-1β, and TNF-α) 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.
Keywords: Cancer; Cytokines; Fatigue; Human papilloma virus; Inflammation; Sickness behavior.
Copyright © 2017 Elsevier Ltd. All rights reserved.
Figures
Fig 1
Inflammation from the tumor propagates to the liver and brain. Tumor tissue expressed high mRNA levels for IL6, IL1β, and TNFα compared to healthy tissue (A). Within tumor-bearing mice, this local inflammation resulted in increased IL6, IL1β, and CD11b mRNA expression in the liver (B) and increased IL1β mRNA within all brain regions tested (C–G). n=6–8/mice group. * p<0.05
Fig 2
Behavioral changes are enhanced in tumor-bearing mice following administration of LPS. An LPS-induced suppression in the rate of nest building was only observed in tumor-bearing mice (A). As we anticipated, tumor-bearing mice showed a reduction in locomotor activity (B). In the non-tumor-bearing mice LPS did not exert a significant effect at 24h, however, an LPS-induced suppression was still observed in the tumor-bearing mice. Immediately after the locomotor activity task, mice were tested in the tail suspension test to assess depressive-like behavior (C). Increased immobility was only observed in the tumor-bearing mice treated with LPS. n=6 mice/group. * p<0.05
Fig 3
Tumor-bearing mice had increased expression of some inflammatory markers following administration of LPS. Within the liver (A), there was effect of the tumor on IL6, IL1β, TNFα, CD11b, and IL1RA; an effect of LPS for TNFα and CD11b, with a trend for IL1RA. Tumor-bearing mice treated with LPS has the highest levels of CD11b (and a trend toward higher IL1R1). Additionally, there was a significant effect of LPS in the non-tumor-bearing mice on TNFα, but this effect was not observed in the already elevated tumor-bearing mice. A similar non-significant trend was observed for IL-1β. Within the cerebellum (B), there was a trend toward an effect of tumor on IL6 and IL1RA as well as an effect of LPS for IL1β, TNFα, and CD11b (a trend for IL1RA). Further, there were higher levels of IL6 and a trend for IL1RA in tumor-bearing mice treated with LPS. Within the frontal cortex of the brain (C), there was an effect of LPS for IL1β and CD11b as well as a trend for TNFα. In tumor-bearing mice there is a trend toward an increase in IL1RA and a trend toward a suppression of CD11b. Within the hippocampus (D), tumor-bearing mice had increased IL1RA and suppressed CD11b, and LPS induced an increase in IL1β, TNFα, and CD11b mRNA expression (trend for IL1RA). There was also a trend toward a greater elevation in IL1RA following LPS in tumor-bearing mice. Within the serum (E), here was a significant effect of tumor on IL6 protein and an effect of LPS, however the LPS effect was more marked in the tumor-bearing mice. n=6 mice/group. Post hoc analyses were conducted when statistically significant main effects or interactions were noted. Lowercase letters in the figure indicate homogenous groups.
Fig 4
Tumor growth and burrowing deficits are attenuated by minocycline treatment. Minocycline treatment resulted in a mild reduction in rate of tumor growth reaching significance on day 21 (A). There was no significant effect of minocycline on body weight (B). Minocycline treatment also significantly attenuated tumor-induced burrowing deficits with effects emerging on day 20 and 28 (C). Two mice, one from each group, required early termination due to rapid tumor growth; missing data values (for day 26/28) were replaced with group means to allow for repeated measures analyses. n=10 mice/group. * p<0.05
Figure 5
Tumor-induced inflammation is attenuated by minocycline treatment. Minocycline treatment significantly reduced IL1β within the liver with a trend toward a reduction in TNFα (A). Further, minocycline resulted in a significant reduction in the expression of CD11b, a marker of activated monocytes, within the liver (likely kupffer cells in this model; Vichaya et al., 2016) (A). Within the brain, minocycline significantly reduced the expression of IL1β mRNA expression (B). Finally, circulating levels of IL6 were significantly reduced following minocycline treatment. n=9 mice/group. * p<0.05
Fig 6
There is no effect of minocycline on tumor growth, body weight, or burrowing behavior in tumor-bearing mice exposed to chemoradiation (CRT). CRT treatment occurred on day 12, 19, and 26 (delineated by arrows in the graphs). As was anticipated, CRT suppressed tumor growth (A); this effect was not modulated by minocycline treatment. Further, there was no effect of minocycline on body weight (B) or on the burrowing deficit induced by Tumor + CRT (C). n=8–9 mice/group.
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