Microglia contribute to mammary tumor-induced neuroinflammation in a female mouse model.

Following diagnosis but before treatment, up to 30% of breast cancer patients report behavioral side effects (e.g., anxiety, depression, memory impairment). Our rodent mammary tumor model recapitulates aspects of these behavioral sequelae, as well as elevated circulating and brain inflammatory mediators. Neuroinflammation is a proposed mechanism underlying the etiology of mood disorders and cognitive deficits, and therefore may be contributing to tumor-associated behavioral side effects. The cellular mechanisms by which tumor-induced neuroinflammation occurs remain unknown, making targeted treatment approaches inaccessible. Here, we tested the hypotheses that microglia are the primary cells driving tumor-induced neuroinflammation and behavioral side effects. Young adult female BALB/c mice were induced with a 67NR mammary tumor; tumor-free controls underwent a sham surgery. Mammary tumors increased IBA1+ and GFAP+ staining in the amygdala and hippocampus relative to tumor-free controls. However, tumors did not alter gene expression of Percoll-enriched microglia isolated from the whole brain. While cognitive, social, and anhedonia-like behaviors were not altered in tumor-bearing mice, tumors increased central tendency in the open-field test; microglia depletion did not reverse this effect. Brain region RT-qPCR data indicated that microglia depletion attenuated tumor-induced elevations of neuroinflammatory gene expression in a region- and mediator-specific manner. These results indicate a causal role of microglia in tumor-induced neuroinflammation. This research advances our understanding of the cellular mechanisms underlying tumor-induced neuroinflammation in order to understand how brain responses (e.g., behavior) may be altered with subsequent cancer-related immune challenges.

Antibiotic treatment inhibits paclitaxel chemotherapy-induced activity deficits in female mice.

Chemotherapy, a mainstay in the treatment of cancer, is associated with severe and debilitating side effects. Side effects can be physical (e.g., gastrointestinal distress, anemia, and hair loss) or mental (e.g., fatigue, cognitive dysfunction). Chemotherapy is known to alter the gut microbiota; thus, communication through the gut-brain axis may influence behavioral side effects. Here, we used a clinically-relevant paclitaxel chemotherapy regimen in combination with antibiotics to test the hypothesis that gut microbes contribute to chemotherapy-associated fatigue-like behaviors in female mice. Data presented suggest that chemotherapy-altered gut microbes contribute to fatigue-like behaviors in mice by disrupting energy homeostasis.

Microglia are implicated in the development of paclitaxel chemotherapy-associated cognitive impairment in female mice.

Chemotherapy remains a mainstay in the treatment of many types of cancer even though it is associated with debilitating behavioral side effects referred to as "chemobrain," including difficulty concentrating and memory impairment. The predominant hypothesis in the field is that systemic inflammation drives these cognitive impairments, although the brain mechanisms by which this occurs remain poorly understood. Here, we hypothesized that microglia are activated by chemotherapy and drive chemotherapy-associated cognitive impairments. To test this hypothesis, we treated female C57BL/6 mice with a clinically-relevant regimen of a common chemotherapeutic, paclitaxel (6 i.p. doses at 30 mg/kg), which impairs memory of an aversive stimulus as assessed via a contextual fear conditioning (CFC) paradigm. Paclitaxel increased the percent area of IBA1 staining in the dentate gyrus of the hippocampus. Moreover, using a machine learning random forest classifier we identified immunohistochemical features of reactive microglia in multiple hippocampal subregions that were distinct between vehicle- and paclitaxel-treated mice. Paclitaxel treatment also increased gene expression of inflammatory cytokines in a microglia-enriched population of cells from mice. Lastly, a selective inhibitor of colony stimulating factor 1 receptor, PLX5622, was employed to deplete microglia and then assess CFC performance following paclitaxel treatment. PLX5622 significantly reduced hippocampal gene expression of paclitaxel-induced proinflammatory cytokines and restored memory, suggesting that microglia play a critical role in the development of chemotherapy-associated neuroinflammation and cognitive impairments. This work provides critical evidence that microglia drive paclitaxel-associated cognitive impairments, a key mechanistic detail for determining preventative and intervention strategies for these burdensome side effects.

Ovarian status modulates endocrine and neuroinflammatory responses to a murine mammary tumor.

Patients with breast cancer have increased circulating inflammatory markers and mammary tumors increase neuroinflammation in rodent models. Menopausal status is not only important in the context of breast cancer as circulating estrogen influences tumor progression, but also because estrogen is anti-inflammatory and an essential modulator of endocrine function in the brain and body. Here, we manipulated "menopause" status (ovary-intact and ovariectomized) in an estrogen receptor (ER)+ mouse mammary tumor model to determine the extent to which ovarian status modulates: 1) tumor effects on estrogen concentrations and signaling in the brain, 2) tumor effects on estrogen-associated neurobiology and inflammation, and 3) the ability for tumor resection to resolve the effects of a tumor. We hypothesized that reduced circulating estradiol (E2) after an ovariectomy exacerbates tumor-induced peripheral and central inflammation. Notably, we observed ovarian-dependent modulation on tumor-induced peripheral outcomes, including E2-dependent processes and, to a lesser degree, circulating inflammatory markers. In the brain, ovariectomy exacerbated neuroinflammatory markers in select brain regions and modulated E2-related neurobiology due to a tumor and/or resection. Overall, our data suggest that ovarian status has moderate implications for tumor-induced alterations in neuroendocrinology and neuroinflammation and mild effects on peripheral inflammatory outcomes in this murine mammary tumor model.

Paclitaxel Chemotherapy Elicits Widespread Brain Anisotropy Changes in a Comprehensive Mouse Model of Breast Cancer Survivorship: Evidence From In Vivo Diffusion Weighted Imaging.

Breast cancer is one of the most common diseases in the United States with 1 in 8 women developing the disease in her lifetime. Women who develop breast cancer are often post-menopausal and undergo a complex sequence of treatments including surgery, chemotherapy, and aromatase inhibitor therapy. Both independently and through potential interactions, these factors and treatments are associated with behavioral comorbidities reported in patients (e.g., fatigue), although the underlying neurobiological mechanisms are poorly understood. Currently, brain imaging is the most feasible way to assess neurobiology in patients. Indeed, breast cancer patients display alterations in white matter connections and chemotherapy is associated with decreased white and gray matter in the corpus callosum and cortex as well as decreased hippocampal volume. However, imaging in breast cancer rodent models is lacking, impeding translation of the mechanistic neurobiological findings made possible through modeling. Furthermore, current rodent models of breast cancer often lack the complexity of typical multimodal breast cancer treatments, thereby limiting translational value. The present study aimed to develop a comprehensive model of post-menopausal breast cancer survival using immunocompetent ovariectomized mice, including an orthotopic syngeneic tumor, surgical tumor removal, chemotherapy, and aromatase inhibitor therapy. Using this model, we systematically investigated the cumulative effects of chemotherapy and hormone replacement therapy on neurostructure and behavior using diffusion weighted imaging, open field test, and spontaneous alternation test. Our previous findings, in a simplified chemotherapy-only model, indicate that this regimen of chemotherapy causes circulating and central inflammation concurrent with reduced locomotor activity. The current study, in the more comprehensive model, has recapitulated the peripheral inflammation coincident with reduced locomotor activity as well as demonstrated that chemotherapy also drives widespread changes in brain anisotropy. Validating the clinical relevance of this comprehensive rodent breast cancer model will allow for additional neurobiological investigations of the interactions among various cancer components associated with behavioral comorbidities, as well as the relationship between these mechanisms and neurostructural imaging changes that can be measured in cancer patients.

Mammary tumors alter the fecal bacteriome and permit enteric bacterial translocation.

BACKGROUND: Cancer patients experience gastrointestinal and behavioral symptoms, and are at increased risk of systemic infection and inflammation. These conditions are a major source of morbidity and decreased quality of life prior to cancer treatment, but poorly defined etiologies impede successful treatment. The gastrointestinal microbiota shape inflammation, influence cancer progression and treatment, and colonize tumors. However, research has not directly determined if peripheral tumors influence the microbiome and intestinal physiology, thus influencing gastrointestinal and behavioral symptoms. Therefore, the purpose of this study was to examine consequences of orthotopic, syngeneic mammary tumor implantation, growth, and resection on fecal bacteriome composition and intestinal barrier function in relation to systemic inflammation and enteric bacterial translocation in mice. METHODS: Female mice were randomized to 3 experimental groups: sham surgical control, tumor recipients, and tumor recipients later receiving tumor-resection. Mice were sacrificed three weeks after tumor implantation or resection for collection of stool, colon, spleen, and brain tissue and analysis. RESULTS: Tumor-bearing mice exhibited several markers of colonic barrier disruption, including dampened expression of tight junction proteins (Cldn1 and Ocln) and elevated circulating lipopolysaccharide binding protein (LBP). Compromised colonic barrier integrity was associated with altered fecal bacterial profiles in tumor-mice, including lower relative abundance of Lactobacillus, but higher Bacteroides. Consistent with colonic barrier disruption and altered microbiomes, tumor-mice displayed markers of systemic inflammation including splenomegaly, higher splenic bacterial load, and elevated splenic and brain pro-inflammatory cytokines. Several  bacteria cultured from spleens had 16S rRNA gene amplicons matching those in fecal samples, suggesting they were of intestinal origin. Fecal Lactobacillus was highly-interrelated to physiological parameters disrupted by tumors via correlation network analysis. Tumor resection ameliorated circulating LBP, splenomegaly, and splenic cytokines, but not other parameters associated with loss of colonic barrier integrity and bacterial translocation. CONCLUSIONS: Orthotopic mammary tumors alter the microbiome, reduce intestinal barrier function, increase translocation of enteric bacteria, and alter systemic inflammation. This provides insight into how tumors commence gastrointestinal and behavioral symptoms prior to treatment, and identify targets for future therapeutics, such as probiotic Lactobacillus supplementation.

A novel targeted approach to delineate a role for estrogen receptor-ß in ameliorating murine mammary tumor-associated neuroinflammation.

PURPOSE: Circulating estrogens in breast cancer patients and survivors are often extremely low due to menopause and estrogen-reducing cancer treatments. Simultaneously, circulating inflammatory markers, and inflammatory proteins in brains of rodent tumor models, can be elevated and correlate with debilitating neurological and psychological comorbidities. Because estrogen has anti-inflammatory properties in the brain, we hypothesized that mammary tumor-induced neuroinflammation is driven, in part, by reduced brain estrogen signaling. METHODS: An ovariectomized mouse model of postmenopausal breast cancer utilizing the ERα-positive 67NR mammary tumor cell line was used for these experiments. A novel, orally bioavailable, and brain penetrant ERß agonist was administered daily via oral gavage. Following treatment, estrogen-responsive genes were measured in brain regions. Central and circulating inflammatory markers were measured via RT-qPCR and a multiplex cytokine array, respectively. RESULTS: We present novel findings that peripheral mammary tumors alter estrogen signaling genes including receptors and aromatase in the hypothalamus, hippocampus, and frontal cortex. Mammary tumors induced peripheral and central inflammation, however, pharmacological ERß activation was not sufficient to reduce this inflammation. CONCLUSIONS: Data presented here suggest that compensating for low circulating estrogen with ERß brain activation is not sufficient to attenuate mammary tumor-induced neuroinflammation, and is therefore not a likely candidate for the treatment of behavioral symptoms in patients. The novel finding that mammary tumors alter estrogen signaling-related genes is a clinically relevant advancement to the understanding of how peripheral tumor biology modulates neurobiology. This is necessary to predict and prevent behavioral comorbidities (e.g., cognitive impairment) prevalent in cancer patients and survivors.

Paclitaxel chemotherapy disrupts behavioral and molecular circadian clocks in mice.

Cancer patients experience circadian rhythm disruptions in activity cycles and cortisol release that correlate with poor quality of life and decreased long-term survival rates. However, the extent to which chemotherapy contributes to altered circadian rhythms is poorly understood. In the present study, we examined the extent to which paclitaxel, a common chemotherapy drug, altered entrained and free-running circadian rhythms in wheel running behavior, circulating corticosterone, and circadian clock gene expression in the brain and adrenal glands of tumor-free mice. Paclitaxel injections delayed voluntary wheel running activity onset in a light-dark cycle (LD) and lengthened the free-running period of locomotion in constant darkness (DD), indicating an effect on inherent suprachiasmatic nucleus (SCN) pacemaker activity. Paclitaxel attenuated clock gene rhythms in multiple brain regions in LD and DD. Furthermore, paclitaxel disrupted circulating corticosterone rhythms in DD by elevating its levels across a 24-hour cycle, which correlated with blunted amplitudes of Arntl, Nr1d1, Per1, and Star rhythms in the adrenal glands. Paclitaxel also shortened SCN slice rhythms, increased the amplitude of adrenal gland oscillations in PER2::luciferase cultures, and increased the concentration of pro-inflammatory cytokines and chemokines released from the SCN. These findings indicate that paclitaxel disrupts clock genes and behavior driven by the SCN, other brain regions, and adrenal glands, which were associated with chemotherapy-induced inflammation. Together, this preclinical work demonstrates that chemotherapy disrupts both central and peripheral circadian rhythms and supports the possibility that targeted circadian realignment therapies may be a novel and non-invasive way to improve patient outcomes after chemotherapy.

Tumor-Induced Cardiac Dysfunction: A Potential Role of ROS.

Cancer and heart diseases are the two leading causes of mortality and morbidity worldwide. Many cancer patients undergo heart-related complications resulting in high incidences of mortality. It is generally hypothesized that cardiac dysfunction in cancer patients occurs due to cardiotoxicity induced by therapeutic agents, used to treat cancers and/or cancer-induced cachexia. However, it is not known if localized tumors or unregulated cell growth systemically affect heart function before treatment, and/or prior to the onset of cachexia, hence, making the heart vulnerable to structural or functional abnormalities in later stages of the disease. We incorporated complementary mouse and Drosophila models to establish if tumor induction indeed causes cardiac defects even before intervention with chemotherapy or onset of cachexia. We focused on one of the key pathways involved in irregular cell growth, the Hippo-Yorkie (Yki), pathway. We used overexpression of the transcriptional co-activator of the Yki signaling pathway to induce cellular overgrowth, and show that Yki overexpression in the eye tissue of Drosophila results in compromised cardiac function. We rescue these cardiac phenotypes using antioxidant treatment, with which we conclude that the Yki induced tumorigenesis causes a systemic increase in ROS affecting cardiac function. Our results show that systemic cardiac dysfunction occurs due to abnormal cellular overgrowth or cancer elsewhere in the body; identification of specific cardiac defects associated with oncogenic pathways can facilitate the possible early diagnosis of cardiac dysfunction.

Voluntary wheel running ameliorates select paclitaxel chemotherapy-induced sickness behaviors and associated melanocortin signaling.

While chemotherapy remains a common cancer treatment, it is associated with debilitating side effects (e.g., anorexia, weight loss, and fatigue) that adversely affect patient quality of life and increase mortality. However, the mechanisms underlying taxane chemotherapy-induced side effects, and effective treatments to ameliorate them, are not well-established. Here, we tested the longitudinal relationship between a clinically-relevant paclitaxel regimen, inflammation, and sickness behaviors (loss of body mass, anorexia, fever, and fatigue) in adult, female mice. Furthermore, we sought to identify the extent to which voluntary exercise (wheel running) attenuates paclitaxel-induced sickness behaviors and underlying central pathways. Body mass and food intake decreased following six doses of chemotherapy treatment relative to vehicle controls, lasting less than 5 days after the last dose. Paclitaxel treatment also transiently decreased locomotion (open field test), voluntary wheel running, home-cage locomotion, and core body temperature without affecting motor coordination (rotarod task). Circulating interleukin (IL)-6 and hypothalamic Il1b gene expression remained elevated in chemotherapy-treated mice at least 3 days after the last dose. Exercise intervention did not ameliorate fatigue or inflammation, but hastened recovery from paclitaxel-induced weight loss. Body mass recovery was associated with the wheel running-induced recovery of body composition, paclitaxel-induced alterations to hypothalamic melanocortin signaling, and associated peripheral circulating hormones (ghrelin and leptin). The present findings demonstrate the benefits of exercise on faster recovery from paclitaxel-induced body mass loss and deficits in melanocortin signaling and suggests the development of therapies targeting the melanocortin pathway to reduce paclitaxel-induced weight loss.

Mammary tumors suppress aging-induced neuroinflammation in female Balb/c mice.

Neuroinflammation confers changes in brain function (i.e., behavior) that are hypothesized to be adaptive in the short-term, but detrimental (e.g., depression, anxiety) if they persist. Both peripheral tumor growth (outside of the brain) and natural aging independently cause neuroinflammation in rodents, which is corroborated by clinical studies. Mammary tumor effects on neuroinflammation and behavior, however, are typically studied in young rodents, whereas most breast cancer patients are middle-aged. Therefore, the existing literature likely underestimates the resulting neuroinflammation that may occur in clinical cancer populations. The present study tested the hypothesis that aging exacerbates mammary tumor-induced neuroinflammation in female mice. Aging (16 months and ovariectomized) increased body and spleen masses, whereas tumors grew faster and increased spleen mass in young mice (12 weeks) only. Tumors (IL-6, IL-10, Tnfα, MCP-1, CXCL1, IP-10) and aging (IL-10, IFNγ) independently increased circulating inflammatory markers, although these variables were only significantly additive in one case (TNFα). In contrast to our prediction, the interaction between tumors and aging resulted in reduced mRNA and protein expression of select inflammatory markers in the hippocampus of tumor-bearing aged mice relative to aged controls. These results indicate that tumors reduce inflammatory activation in the brains of aged mice, a deficit that is likely disadvantageous. Further understanding of how aging and cancer interact to affect brain function is necessary to provide clinically-relevant results and identify mechanisms underlying persistent behavioral issues hampering adult cancer patients.

Mammary tumors compromise time-of-day differences in hypothalamic gene expression and circadian behavior and physiology in mice.

Circadian rhythms influence various aspects of biology, including hormonal, immunological, and behavioral processes. These 24-hour oscillations are necessary to optimize cellular functions and to synchronize these processes with the environment. Breast cancer patients and survivors frequently report disruptions in circadian oscillations that adversely affect quality-of-life, including fragmented sleep-wake cycles and flattened cortisol rhythms, which are associated with negative behavioral comorbidities (e.g., fatigue). However, the potential causal role of tumor biology in circadian dysregulation has not been investigated. Here, we examined the extent to which sham surgery, non-metastatic mammary tumors, or mammary tumor removal in mice disrupts circadian rhythms in brain clock gene expression, locomotor behavior (free-running and entrained), and physiological rhythms that have been associated with cancer behavioral comorbidities. Tumors and tumor resection altered time-of-day differences in hypothalamic expression of eight circadian-regulated genes. The onset of activity in entrained running behavior was advanced in tumor-bearing mice, and the amplitude of free-running rhythms was increased in tumor-resected mice. Tumors flattened rhythms in circulating corticosterone and Ly6cHi monocytes which were largely restored by surgical tumor resection. This work implies that tumors alone may directly impact central and/or peripheral circadian rhythmicity in breast cancer patients, and that these effects may persist in cancer survivors, potentially contributing to behavioral comorbidities.

Cancer and cancer survival modulates brain and behavior in a time-of-day-dependent manner in mice.

Improvements in breast cancer therapy/diagnosis have substantially increased the cancer survivor population, although many survivors report persistent mental health issues including fatigue, mood and anxiety disorders, and cognitive impairments. These behavioral symptoms impair quality-of-life and are often associated with increased inflammation. Nocturnal rodent models of cancer are critical to the identification of the neurobiological mechanisms underlying these behavioral changes. Although both behavior and immunity display distinct diurnal patterns, most rodent research in this field is performed during the rodents' inactive (light) period, which could potentially undermine the conclusions and clinical relevance. Therefore, here we tested the extent to which mammary tumors or tumor resection ("survivors") in mice affects behavior and neuroinflammation in a nyctohemeral (day versus night)-dependent manner. Indeed, only the dark (active) phase unmasked fatigue-like behavior and altered novel object investigation for both tumor-bearing and -resected mice relative to surgical controls. Several inflammatory markers were expressed in a time-of-day-dependent manner (lower in the dark phase) in the blood and brains of surgical control mice, whereas this temporal pattern was absent (IL-1ß, CXCL1, Myd88, Cd4) or reversed (C3) in the respective tissues of tumor-bearing and -resected mice. Taken together, these data indicate that the time of day of assessment significantly modulates various persistent and transient tumor-induced behavioral and immune changes.

Tumor resection ameliorates tumor-induced suppression of neuroinflammatory and behavioral responses to an immune challenge in a cancer survivor model.

Breast cancer survivors display altered inflammatory responses to immune challenges relative to cancer-naive controls likely due to previous cancer treatments, stress associated with cancer, and/or tumor physiology. Proper inflammatory responses are necessary for adaptive sickness behaviors (e.g., fatigue, anorexia, and fever) and neuroinflammatory pathways are also implicated in mental health disturbances (e.g., cognitive impairment, depression) suffered by cancer patients and survivors. Rodent cancer models indicate that tumors are sufficient to exacerbate neuroinflammatory responses after an immune challenge, however primary tumors are not usually present in cancer survivors, and the behavioral consequences of these brain changes remain understudied. Therefore, we tested the extent to which mammary tumor resection attenuates tumor-induced neuroinflammation and sickness behavior following an immune challenge (i.p. lipopolysaccharide [LPS] injection) in mice. Tnf-α, Il-1ß, and Il-6 mRNA decreased in multiple brain regions of LPS-treated tumor-bearing mice relative to LPS-treated controls; tumor resection attenuated these effects in some cases (but not Tnf-α). Tumors also attenuated sickness behaviors (hypothermia and lethargy) compared to LPS-treated controls. Tumor resection reversed these behavioral consequences, although basal body temperature remained elevated, comparable to tumor-bearing mice. Thus, tumors significantly modulate neuroinflammatory pathways with functional consequences and tumor resection mitigates most, but not all, of these changes.

Sexual activity modulates neuroinflammatory responses in male rats.

Immune activity influences reproduction, however, the extent to which mating experience may inversely alter immune pathways is poorly understood. A few studies in humans suggest that mating triggers a circulating immune and hypothalamic-pituitary-adrenal axis response. In male rats, mating experience enhances neuroplasticity and improves cognitive function and affective-like behavior, independent of the physical activity component. Yet, the extent to which mating experience may influence immune responses in the brain remain unexplored. Here, we hypothesized that recent mating experience in male rats increases neuroinflammatory signaling (via lipopolysaccharide [LPS] stimulation, i.p.) and associated sickness behaviors (i.e., food intake, weight loss) relative to sexually-naïve controls. Virgin male rats were exposed to a sexually non-receptive (control) or sexually-receptive female for 30 min for six consecutive days. Immediately following the last mating experience, rats were administered a saline or LPS injection and euthanized four hours later. Mating increased Tnfα responses to LPS in the brain, which positively correlated with LPS-induced weight loss. Mating also increased peripheral corticosterone among saline-treated rats, but this corticosterone response was attenuated in the most proficient copulators (e.g., shortest latencies). Thus, recent mating experience may be a unique modulator of select stimulated inflammatory signals that are relevant to adaptive neuroimmune responses and behavior.

Gut microbiota-immune-brain interactions in chemotherapy-associated behavioral comorbidities.

Increasing scientific attention is focused on the gut-brain axis, including the ability of the gastrointestinal (GI) tract to modulate central nervous system function. Changes in the intestinal microbiome can influence affective-like behavior, cognitive performance, fatigue, and sleep in rodents and humans. Patients with cancer who are receiving chemotherapy experience similar negative behavioral changes and concurrent GI symptoms. These chemotherapy comorbidities can be long-lasting and may reduce patients' quality of life and motivation to comply with treatment. This review summarizes the clinical and preclinical evidence supporting a role for the intestinal microbiome in mediating behavioral comorbidities through peripheral immune activation in patients with cancer who are receiving chemotherapy. In addition, evidence suggesting that targeted modification of the intestinal microbiome during cancer treatment could ameliorate associated behavioral comorbidities is reviewed.

Neuroimmunology of Behavioral Comorbidities Associated With Cancer and Cancer Treatments.

Behavioral comorbidities (depression, anxiety, fatigue, cognitive disturbances, and neuropathic pain) are prevalent in cancer patients and survivors. These mental and neurological health issues reduce quality-of-life, which is a significant societal concern given the increasing rates of long-term survival after various cancers. Hypothesized causes of behavioral comorbidities with cancer include tumor biology, stress associated with the cancer experience, and cancer treatments. A relatively recent leading mechanism by which these causes contribute to changes in neurobiology that underlie behavior is inflammation. Indeed, both basic and clinical research indicates that peripheral inflammation leads to central inflammation and behavioral changes in other illness contexts. Given the limitations of assessing neuroimmunology in clinical populations, this review primarily synthesizes evidence of neuroimmune and neuroinflammatory changes due to two components of cancer (tumor biology and cancer treatments) that are associated with altered affective-like or cognitive behaviors in rodents. Specifically, alterations in microglia, neuroinflammation, and immune trafficking to the brain are compiled in models of tumors, chemotherapy, and/or radiation. Evidence-based neuronal mechanisms by which these neuroimmune changes may lead to changes in behavior are proposed. Finally, converging evidence in clinical cancer populations is discussed.

Effects of dermal wounding on distal primary tumor immunobiology in mice.

BACKGROUND: Before primary oral tumors are treated, various prophylactic procedures that require tissue repair are often necessary (e.g. biopsies, tooth extractions, radiation, and tracheotomies). Wound healing and tumor growth harness similar immune/inflammatory mechanisms. Our previous work indicates that tumors impair wound healing, although the extent to which tissue repair conversely influences tumor growth is poorly understood. Here, we test the hypothesis that dermal wound healing exacerbates primary tumor growth and influences tumor immunobiology. MATERIALS AND METHODS: Female, immunocompetent mice were inoculated subcutaneously with murine oral cancer cells (AT-84) to induce flank tumors. Half of the mice received dermal excisional wounds (4 × 3.5 mm diameter) on their dorsum 16 days later, whereas the skin of controls remained intact. Tumor and blood tissues were harvested 1 and 5 days post wounding, and tumor myeloid cell populations and inflammatory gene expression were measured. Circulating myeloid cells, cytokines, and corticosterone were also quantified. RESULTS: Wounding increased tumor mass, early tumor infiltration of macrophages, and tumor inflammatory gene expression. While wounding attenuated tumor growth-induced increases in circulating myeloid cells, no effects of wounding on circulating cytokine/endocrine measures were observed. CONCLUSIONS: These results indicate that modest skin immune/inflammatory processes can enhance distal tumor growth and alter innate tumor immunity. The implication for this work is that, in the presence of a tumor, the benefits of tissue-damaging procedures that occur clinically must be weighed against the potential consequences for tumor biology.

Euflammation Attenuates Central and Peripheral Inflammation and Cognitive Consequences of an Immune Challenge after Tumor Development.

OBJECTIVE: Repeated subthreshold bacterial exposures in rodents cause novel euflammation that attenuates neuroinflammation and sickness behaviors upon subsequent infectious challenges to the host without eliciting illness behavior. The investigation of bacterial exposure effects on brain and behavior is clinically relevant because bacterial-based antitumor treatments are used successfully, but are suboptimal due to their illness side effects. In addition, behavioral consequences (depression, cognitive impairments) to homeostatic challenges that are associated with inflammation are prevalent and reduce the quality of life in cancer patients and survivors. Therefore, this study tested the potential for euflammation to attenuate behavioral consequences of an immune challenge in tumor-bearing mice. METHODS: Mice with and without oral tumors in their flank underwent the established peripheral euflammatory protocol or vehicle treatment, followed by an acute peripheral immune challenge (lipopolysaccharide [LPS] injection) or PBS. Cognitive function and sickness behavior were assessed after the challenge, and peripheral and central inflammatory responses were measured. RESULTS: Euflammation reduced LPS-induced peripheral and central inflammation in all mice; however, neuroinflammation was less attenuated in tumor-bearing mice compared with tumor-free controls. LPS-induced lethargy and cognitive impairments were more pronounced among tumor-bearing mice and were effectively attenuated with euflammation. Cognitive changes were independent of brain-derived growth factor gene expression in the hippocampus. CONCLUSION: These results suggest that induction of euflammation may be useful in alleviating the negative side effects of bacterial-based tumor treatments and in potentially attenuating common behavioral comorbidities associated with cancer or other chronic diseases.

Novel rodent model of breast cancer survival with persistent anxiety-like behavior and inflammation.

Breast cancer survivors are an expanding population that is troubled by lasting mental health problems, including depression and anxiety. These issues reduce quality-of-life throughout survivorhood. Research indicates that tumor biology, cancer treatments, and stress contribute to these mood disturbances. Although the mechanisms underlying these various causes remain under investigation, neuroinflammation is a leading hypothesis. To date, rodent models of recurrence-free tumor survival for understanding mechanisms by which these behavioral issues persist after cancer are lacking. Here, we test the extent to which potential behavioral symptoms persist after mammary tumor removal in mice (i.e., establishment of a cancer survivor model), while also empirically testing the causal role of tumors in the development of neuroinflammatory-mediated affective-like behaviors. Complete surgical resection of a non-metastatic orthotopic, syngeneic mammary tumor reversed tumor-induced increases of circulating cytokines (IL-6, CXCL1, IL-10) and myeloid-derived cells and modulated neuroinflammatory gene expression (Cd11b, Cxcl1). Multiple anxiety-like behaviors and some central and peripheral immune markers persisted or progressed three weeks after tumor resection. Together, these data indicate that persistent behavioral changes into cancer survivorhood may be due, in part, to changes in immunity that remain even after successful tumor removal. This novel survivor paradigm represents an improvement in modeling prevalent cancer survivorship issues and studying the basic mechanisms by which cancer/cancer treatments influence the brain and behavior.