Abstract SY31-02: Behavioral consequences of peripheral tumors: Neuroimmune mechanisms

In cancer patients, depression, anxiety and cognitive impairment comorbidities are associated with decreased cancer survivorship and increased treatment noncompliance. These comorbidities are assumed to be either (1) a consequence of an individuals’ knowledge that s/he has been diagnosed with a life-threatening disease or (2) a consequence of chemotherapeutic treatments. In part, perhaps, because of these assumptions, the issues of whether and how tumors alone affect brain function have remained more or less entirely neglected. My work is influenced by the established body of psychoneuroimmunology research indicating that acute peripheral infection triggers production of cytokines, which act in the brain to induce transient states of depression and cognitive impairment. In common with acute infections, tumors also produce cytokines, but they do so over a more prolonged duration. Here we are the first to examine the extent to which and how tumor-derived cytokines contribute to cancer-induced behavioral comorbidities. In our first studies, we show that rats with carcinogen-induced (N-nitroso-N-methylurea) mammary cancer exhibit depression- and anxiety-like behaviors in the absence of overt sickness behaviors using standard behavioral tests of these behaviors. The production of proinflammatory cytokines, known to induce depressive-like behaviors, was also found to be elevated in the tumors and blood (IL-1β), and in a brain region that regulates emotional and cognitive behavior (hippocampus; IL-1, IL-6, TNFα) of rats with tumors compared with controls. In tumor-bearing rats, circulating corticosterone, which is an established inhibitor of cytokine signaling, was suppressed following a stressor, and gene expression of hippocampal glucocorticoid receptors was elevated. The results establish that tumors alone are sufficient to trigger changes in emotional behaviors. Dampened glucocorticoid responses to stressors may exacerbate the deleterious effects of tumor-induced cytokines on affective state. Cancer is also associated with serious and problematic cognitive impairments. In the next studies, we tested the hypothesis that endogenous biological factors arising from tumor development (i.e., cytokines) may also play a causal role in these cognitive impairments. Rats with carcinogen-induced mammary tumors exhibited impaired spatial reference memory on a radial arm maze and amnesia for familiar objects in an object recognition memory test. In contrast, their learning in the aversive hippocampal-dependent Morris water maze and in fear conditioning tests was comparable to that of controls. These select cognitive impairments were accompanied by elevations in hippocampal IL-1β mRNA expression, but were not associated with decreases in hippocampal brain-derived neurotrophic factor gene expression. Together, the results indicate that peripheral tumors alone are sufficient to induce increases in hippocampal cytokine expression and select deficits in hippocampal-dependent memory tasks. Given our findings that mammary tumors in rats induce proinflammatory cytokine production in the brain and that cytokines have been shown to have functional consequences in the brain, we then explored the potential underlying neuroimmune mechanisms in the brain. We began by using the expanding information on neuroimmune mechanisms by which acute, peripheral bacterial infections alter behavior as a starting point. The study of acute illness indicates that brain inflammatory signaling is triggered via neural and humoral routes from the periphery and prime or activate the resident immune cells in the brain, microglia. Activated brain microglial cells produce exaggerated cytokine responses associated with emotional behaviors and cognitive disruption. Inflammatory cytokines then trigger a cascade of inflammatory signaling gene transcription often regulated by NF-κB. One of the such genes transcribed that is mechanistically linked to depressive-like behavior is indolamine 2,3-deoxygenase (IDO). IDO activity reduces serotonin production, a phenomenon thought to drive behavioral depression. Therefore, our next experiments tested whether tumors activate microglia or prime microglia to subsequent homeostatic challenges, and thereby initiate an inflammatory signaling cascade shown to regulate depressive-like behavior. Perfused brains from rats with carcinogen-induced mammary cancer were examined 3 weeks after tumors were detected. Rats also received lipopolysaccharide (LPS; i.p., 250 μg/kg) or saline treatment 4 or 24 h prior to brain collection to identify changes in neuroinflammatory markers in response to an immune challenge that may be otherwise masked under basal conditions. A microglial marker (CD11b), pro-inflammatory cytokines, IDO, and NF-κB-related genes expression was measured in brain regions that regulate emotional and cognitive behaviors (hippocampus, hypothalamus, and frontal cortex) by qPCR. Tumors exacerbated LPS-induced microglial, IL-1β, IDO, and NF-κB gene expression primarily in the hippocampus at the time when depressive-like behaviors have been observed. These data indicate that peripheral tumors induce inflammatory signaling in the brain that may underlie some negative behavioral comorbidities commonly comorbid with cancer. In the final experiments, we sought to extend existing information demonstrating that measures of the nervous and endocrine systems are predictive of survival outcomes after a chronic disease is diagnosed. Our unique approach was to determine biomarkers that predict risk before chronic disease development using the carcinogen-induced rat model of breast cancer. In this study, natural variation in circulating corticosterone and depressive-like behaviors (using the Porsolt forced swim test) were measured in female Wistar rats before induction of mammary tumors. Early tumor onset after carcinogen treatment was associated with relatively high basal depressive-like behavior and relatively low basal corticosterone concentrations. These results suggest that the susceptibility to tumor initiation and/or growth may be related to individual differences in physiology and emotional tone present at the time of carcinogen exposure. In summary, this project has begun to explore the role of cancer itself on behavioral comorbidities associated with cancer from a neuroimmune perspective. Future studies will incorporate the role of stress associated with cancer diagnosis in the model. Insights gleaned from this work have the potential to alter the current treatments of behavioral comorbidities associated with cancer and to provide biomarkers to use in prophylactic approaches to cancer treatment. These expected outcomes will substantially improve the quality of life for the growing population of cancer survivors and will fundamentally advance the field of psychoneuroimmunology. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY31-02. doi:1538-7445.AM2012-SY31-02