pre-treatment effects of peripheral tumors on brain and behavior: … · 2017. 12. 22. · the...

Brain, Behavior, and Immunity 49 (2015) 1–17

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Brain, Behavior, and Immunity

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Invited Review

Pre-treatment effects of peripheral tumors on brain and behavior:Neuroinflammatory mechanisms in humans and rodents

http://dx.doi.org/10.1016/j.bbi.2015.04.0100889-1591/� 2015 Elsevier Inc. All rights reserved.

⇑ Corresponding author at: Ohio State University, 219 Institute for BehavioralMedicine Research, 460 Medical Center Dr., Columbus, OH 43210, USA. Tel.: +1 614293 3496; fax: +1 614 366 2097.

E-mail address: [email protected] (L.M. Pyter).

Andrew Schrepf a, Susan K. Lutgendorf a,b, Leah M. Pyter c,⇑a Department of Psychology, University of Iowa, Iowa City, IA 52242, USAb Departments of Urology and Obstetrics and Gynecology, University of Iowa, Iowa City, IA 52242, USAc Institute for Behavioral Medicine Research, Departments of Psychiatry and Behavioral Health and Neuroscience, Ohio State University, Columbus, OH 43210, USA

a r t i c l e i n f o

Article history:Received 13 February 2015Received in revised form 14 April 2015Accepted 17 April 2015Available online 6 May 2015

Keywords:CancerDepressionCognitionCytokines

a b s t r a c t

Cancer patients suffer high levels of affective and cognitive disturbances, which have been attributed todiagnosis-related distress, impairment of quality of life, and side effects of primary treatment. An inflam-matory microenvironment is also a feature of the vast majority of solid tumors. However, the ability oftumor-associated biological processes to affect the central nervous system (CNS) has only recently beenexplored in the context of symptoms of depression and cognitive disturbances. In this review, wesummarize the burgeoning evidence from rodent cancer models that solid tumors alter neurobiologicalpathways and subsequent behavioral processes with relevance to affective and cognitive disturbancesreported in human cancer populations. We consider, in parallel, the evidence from human clinical cancerresearch demonstrating that affective and cognitive disturbances are common in some malignanciesprior to diagnosis and treatment. We further consider the underlying neurobiological pathways,including altered neuroinflammation, tryptophan metabolism, prostaglandin synthesis and associatedneuroanatomical changes, that are most strongly implicated in the rodent literature and supported byanalogous evidence from human cancer populations. We focus on the implications of these findingsfor behavioral researchers and clinicians, with particular emphasis on methodological issues and areasof future research.

� 2015 Elsevier Inc. All rights reserved.

1. Introduction

Cancer patients suffer from a high prevalence of depression,anxiety, and cognitive disturbances (Evans et al., 2005). In fact,these disturbances are common among numerous other popula-tions with chronic, inflammatory disease (e.g, cardiovascular dis-ease, metabolic disease, HIV/AIDS), a fact that has stimulateddiscussion of potential shared biological mechanisms (Irwin andMiller, 2007; Lee et al., 2004). In the field of cancer research, it iswidely acknowledged that various interrelated factors mayunderlie these behavioral comorbidities: tumor biology, distressassociated with the cancer diagnosis, and/or cancer treatments(e.g., ‘‘chemobrain’’). However, in spite of a recent burst of researchactivity in this area, these factors are rarely differentiated and theirlikely mechanistic interactions remain either entangled or ignored

(Dantzer et al., 2012). For example, many clinical cancer studies donot encompass pre-diagnosis or pre-treatment psychological orphysiological measures and most rodent studies of the impact ofcancer treatment on the central nervous system (CNS) usetumor-free models. This results in a knowledge gap concerningthe independent impact of tumor-associated biological processeson affective and cognitive symptoms despite the acknowledgmentthat tumors are capable of exerting an influence on the CNS(Cleeland et al., 2003; Lee et al., 2004), and that inflammation isinherent to all phases of tumor growth and metastases (Colottaet al., 2009). Addressing this deficit will help to identify specificunderlying biological causes and mechanisms ofcancer-associated affective and cognitive disturbances, with thepotential to improve treatment.

This knowledge gap by presenting the current literature on thepotential for tumor-associated biological processes to affect brainfunction (affect and cognition) independent of cancer-associatedstress and treatments. We focus on behavioral changes that aremost strongly associated with the presence of a tumor outside ofthe CNS and on identifying underlying mechanisms using data

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Box 1. Roles of classical neuroinflammatory markers in behavior.

Cytokines

� Regulate inflammation via their production and release byimmune cells.� Negatively regulated by glucocorticoids (Barnes, 1998;

Goujon et al., 1997).� Produced by microglia, astrocytes, endothelial cells, and neu-

rons in brain regions that regulate behavior (hippocampus,hypothalamus, cortex, nucleus of the solitary tract, medulla;Dantzer et al., 2008).� Activate other inflammatory mediators (prostaglandins,

NF-kB, COX-2, IDO, iNOS; Salazar et al., 2012).� Alter neurotransmitter signaling, neuroendocrine axes, and

neural plasticity (Miller et al., 2009).� Demonstrated role in rodent models of sickness, affective

and cognitive impairment behaviors (reviews see Dantzeret al., 2008; Donzis and Tronson, 2014; Neveu and Liège,2000; York et al., 2012).� Implicated in behavioral changes following inflammatory

events; associated with mental illness diagnoses (reviewssee Dantzer et al., 2008; DellaGioia and Hannestad, 2010;Donzis and Tronson, 2014; York et al., 2012).

NF-kB

� Pro-inflammatory transcription factor family triggered bycytokines in both the peripheral and brain.� Implicated in periphery-to-brain inflammatory signaling

(Godbout et al., 2005; Nadjar et al., 2003; Quan et al., 1997).� Necessary for cytokine-induced changes in emotional and

cognitive behaviors in rodents (Nadjar et al., 2003; Nadjaret al., 2005).� Elevated in peripheral blood mononuclear cells of patients

with depression (Pace et al., 2006).

COX-2/prostaglandins

� Produced once cytokines receptors are activated in endothe-lial cells, neurons, and microglia in the brain (Bluthé et al.,1992).� Cytokine-inducible, COX-2, is a key enzyme involved in pros-

taglandin synthesis from arachidonic acid (Masferrer et al.,1992).� Established targets of anti-inflammatory pharmaceuticals

(Chakraborti et al., 2010).� Upregulation of COX-2 and PGE2 synthesis in the blood and

CNS has been correlated with depression in human (Liebet al., 1983) and non-human studies (Cassano et al., 2006;Guo et al., 2009).

2 A. Schrepf et al. / Brain, Behavior, and Immunity 49 (2015) 1–17

from human and rodent research. Direct effects of tumor associ-ated biological processes on the brain would indicate that patientssuffer affective and cognitive disturbances prior to the receipt oftreatment. The clinical impact of psychological comorbiditiesshould not be underestimated in the context of cancer. Both qual-ity of life and adherence to treatment plans significantly deterio-rate when depression and other mood disturbances are present(DiMatteo, 2003). Poor treatment adherence is a significant riskfactor for decreased quality of life and increased mortality (Grippet al., 2007). Isolating the specific influence of tumor biology onCNS processes and empirically testing how tumor biology interactswith the biology of stress and cancer treatments may allow for tai-lored treatment of cancer-associated affective and cognitivecomorbidities. This review first provides a brief summary ofinflammation-induced changes in behavior, and then summarizesthe quickly growing body of behavioral research in rodent cancermodels and clinical investigations of cancer patients prior to treat-ment. Evidence for affective and somatic symptoms of depression,cognitive impairment, and their mechanistic correlates arereviewed.

1.1. Inflammation-induced behavioral changes

There is now considerable evidence that inflammatory path-ways modulate affective and cognitive processes (Dantzer et al.,2008; Maes et al., 2012; Miller et al., 2009). Various aspects of thisconcept have been termed the ‘‘cytokine’’ or ‘‘macrophage theoryof depression’’ and ‘‘sickness behavior.’’ These concepts are primar-ily supported by literatures demonstrating that: (1) pathways existbetween the periphery and CNS that allow for modulation of neu-ral structure and function (e.g., enhanced permeability of theblood–brain-barrier and signaling via the vagus nerve; Dantzeret al., 1999), (2) acute cytokine or bacterial mimetic injection inrodents (i.p. lipopolysaccharide [LPS]; Dantzer et al., 2008) inducesbehavioral changes that are reversible by anti-inflammatory phar-macologic treatment, (3) inflammatory/immune responses andmarkers are elevated in patients with psychological disorders suchas major depressive disorder (Maes et al., 2012; Miller et al., 2009)and, (4) anti-inflammatory drugs can be efficacious in the treat-ment of some psychiatric disorders (Köhler et al., 2014). For exam-ple, patients with clinical depression display elevations inproinflammatory cytokine concentrations in the blood and cerebralspinal fluid, increases in other circulating inflammatory effectorand target molecules (e.g., prostaglandins, acute phase proteins,chemokines, cell adhesion molecules; Maes et al., 2012) andaltered adaptive immune cell function (Howren et al., 2009;Miller, 2010). Cytokine-based treatment of cancers (i.e.,interferon-alpha) also result in considerable increases in depres-sion (Capuron et al., 2002; Udina et al., 2012), which resolve whenthe treatment is terminated.

Studies using animal models have delineated inflammatorymechanisms underlying changes in behavior, including sicknessbehavior, affective symptoms, and cognitive function. However,the majority of the research in this area has focused on modelsof acute illness. The canonical acute bacterial infection model, asingle, sub-toxic i.p. injection of LPS (a component of the cell wallof Escherichia coli bacteria), causes proinflammatory cytokine pro-duction primarily by first-responder monocytes in the peritonealcavity. Then, through both neural and humoral signaling pathways(Dantzer et al., 2008; Quan and Banks, 2007; Quan, 2014), cytokineproduction rapidly ensues in the brain (hippocampus, hypothala-mus, forebrain) and stimulates the production or activation ofother inflammatory effectors (IDO, iNOS, Nf-KB, COX; Quan et al.,1998). The roles of these inflammatory markers incytokine-induced behavioral changes, and consistent with clinicalresearch in depressed patients, are summarized in Box 1. Acute

sickness behaviors (e.g., lethargy, social withdrawal, fever, anorex-ia) akin to ‘‘somatic’’ or ‘‘vegetative’’ symptoms of depression, sub-sequent affective-like behaviors, and impaired learning andmemory (Pugh et al., 1998) follow for several days after LPS treat-ment. The experimental manipulation of cytokines in these models(e.g., pharmacologic blockade, cytokine gene knockout) has estab-lished that brain-production of cytokines are necessary and suffi-cient for the subsequent behavioral changes (Dantzer et al., 1998,1999; Kent et al., 1992). As with all preclinical studies, there isthe assumption that affective-like behaviors assessed by rigorouslyvalidated rodent behavioral tests (Dantzer et al., 2012) are analo-gous to some affective symptoms of depression in human beings.

� Potentially also affects cognition (Savonenko et al., 2009;Yirmiya and Goshen, 2011).

Indolamine-2,3-deoxygenase

� Increased centrally in response to peripheral cytokineproduction.� Shunts tryptophan metabolism toward kynurenine produc-

tion and away from serotonin production (Dantzer et al.,2008).� Blocking IDO attenuates LPS- and BCG-induced behavioral

consequences (O’Connor et al., 2009a,b).� Chronic and acute illnesses in humans activate IDO in the

periphery (Wirleitner et al., 2003).� Circulating tryptophan depletion is reported in depressed

patients (Ruhé et al., 2007; Wichers et al., 2005) andcognitively-impaired Alzheimer’s patients (Gulaj et al.,2010).

A. Schrepf et al. / Brain, Behavior, and Immunity 49 (2015) 1–17 3

A longer-enduring infectious disease model (i.p., injection ofBacillus Calmette-Guerin [BCG]) has been used to probe for differ-ences in chronic versus acute bacterial illness. Like the LPS model,BCG induces depressive-like behaviors after overt sickness behav-iors have subsided. Coincident with the behavioral changes, theBCG model triggers brain cytokine and IDO production (Lestageet al., 2002; Moreau et al., 2005). While longer-lasting than theLPS model, the behavioral and inflammatory consequences ofBCG infection still last only 3–4 weeks (Moreau et al., 2008).

In summary, the majority of the mechanistic postulating aboutmental comorbidities within the cancer context (and other chronicinflammatory diseases) logically focuses on neuroinflammatorypathways (Cleeland et al., 2003; Dantzer et al., 2012; Illmanet al., 2005; Lee et al., 2004). Peripheral tumors and their microen-vironment are sources of various cytokines and potentially useneural and/or humoral signaling pathways similar to peripheralinfection to gain access to the brain. A review of the current liter-ature that best encapsulates the purely biological influence ofperipheral tumors on brain physiology and depression and cogni-tion follows. Here we organized the corresponding behavioral datafrom rodent and human research and discuss the putative inflam-matory mechanisms associated with these behaviors. Finally, wediscuss how this compilation of data may be used to modify cur-rent treatment strategies and future research design in an effortto move towards more individualized, mechanism-based treat-ment approaches.

2. Rodent models of cancer

Recent basic research in rodents provides compelling evidencethat primary tumors and tumor-associated inflammation alterbrain physiology and behavior. Essentially, these models are com-parable to patients with cancer prior to treatment, though bothhuman and rodent research reflects considerable heterogeneityin the type and timing of neoplasms investigated. Rodent modelingallows for both the differentiation of potentially additive/synergis-tic biopsychological factors and for the empirical study of underly-ing mechanisms. For the purpose of this review, we focused onPubMed primary reports in the English language of rodent modelswith malignant primary tumors outside of the CNS, using thesearch terms [‘‘rodent;’’ ‘‘cancer’’ or ‘‘tumor;’’ ‘‘inflammation’’ or‘‘cytokine’’ or ‘‘neuroinflammation’’ or ‘‘serotonin;’’ ‘‘behavior’’ or‘‘cognition’’ or ‘‘learning’’ or ‘‘affect’’ or ‘‘depression’’ or ‘‘anxiety,

indexed from ‘‘no determined start date’’ to January, 2015].Additional criteria were that the reports included tumor-freecontrol groups and groups in which both cancer therapies andpsychosocial stressors were absent.

2.1. Evidence for inflammation in tumor-bearing rodent models

In rodent models of solid neoplasms, tumor cells, surroundingstromal cells, and leukocytes recruited to the tumor site producemany inflammatory mediators (cytokines, chemokines) in thetumor microenvironment (reviewed in Allavena et al., 2008a;Allavena et al., 2008b; Candido and Hagemann, 2013; Coussensand Werb, 2002). Commonly identified inflammatory mediatorsinclude various cytokines, chemokines, and their receptors (e.g.,IL-1, TNFa, IL-6, IL-10, IL-12, TGFb, MIP1a, CXCR4; Candido andHagemann, 2013; Turrin et al., 2004), prostaglandin E2, NF-jBand STAT3 signaling cascades, and enzymes such as IDO, COX,and iNOS (reviewed in Cesario et al., 2011; Karin et al., 2002;Landskron et al., 2014; Munn and Mellor, 2013; Uyttenhoveet al., 2003). Cytokine production in the tumor microenvironmentis sometimes significant enough to be detectable in the general cir-culation of experimental models (Fang et al., 2012; Lamkin et al.,2011; Norden et al., 2015; Uomoto et al., 1998; Yang et al.,2014). However, this detection appears to be dependent upon thetype of tumor and the timing of the blood sampling relative totumor growth, as elevations in circulating cytokines do not neces-sarily accompany elevations in tumor cytokines, brain cytokines, orbehavioral changes in these models (Catalano et al., 2003; Pyteret al., 2009). Given the known interactions between the HPA axisand inflammatory responses, it is important to note that solidtumors either increase or have no effect on basal circulating corti-costerone concentrations (Azpiroz et al., 2008; Bojková et al., 2011;Chuluyan et al., 2000; Pyter et al., 2009; Yang et al., 2014), decreasestressor-triggered corticosterone responses (Pyter et al., 2009), andincrease glucocorticoid receptor expression in brain regionsinvolved in the HPA axis negative feedback loop (Pyter et al.,2009) in some rodent models.

2.2. Sickness, affective-like and cognitive impairment behaviors intumor-bearing rodent models

In rodents, many somatic-like symptoms of depression haveconsiderable overlap with ‘‘sickness behaviors’’ (e.g., food intake,physical activity, motivation for social interaction). Several tumormodels have been developed specifically for their extreme negativeeffects on food intake, weight loss, and muscle wasting (Emery,1999; Tisdale, 2002). More broadly, however, in studies of tumormodels that focus on other behaviors (e.g., affective-like), weightloss ranges widely from significant (Lamkin et al., 2011; Nordenet al., 2015; Wang et al., 2001; Yang et al., 2014) to absent(Coma et al., 2003; Pyter et al., 2009), depending on the tumortype, the rate of tumor growth and the time of assessment. Inone study, total weight loss includes a specific reduction in brainmass (Coma et al., 2003).

The weight loss observed in some models is coincident withelectrophysiological muscle fatigue (Aulino et al., 2010; Baltgalviset al., 2010; Murphy et al., 2012; Norden et al., 2015), reduced loco-motor activity (Lamkin et al., 2011; Murphy et al., 2012; Xiu et al.,2010), and reduced voluntary wheel running (Baltgalvis et al.,2010; Wood et al., 2006). Reduced locomotor activity may reflectfatigue or physical limitations due to the tumor location and/orchanges in areas of the CNS that regulate movement (Dantzeret al., 2012). While the tumor may infringe on physical movementor muscle endurance in some models, thereby confounding resultsof affective-like or cognitive behavioral testing, depressive-likebehaviors persist in other tests that are virtually independent of


locomotion (e.g., sucrose anhedonia, see below). In contrast, theeffects of peripheral tumors on sleep, a component of fatigue,remain understudied. Finally, limited investigation of social with-drawal, a common component of sickness behavior, indicates thattumor-bearing rodents are no less interested in social interactions(Pyter et al., 2009) or E2-primed lordosis with a mate (Walf andFrye, 2010) than their tumor-free counterparts.

In contrast to tumor-associated sickness behaviors, the vastmajority of studies to examine affective-like or cognitive behaviorsin cancer models were published within the last five years, except-ing some research in the 1970s–80s on learned taste aversion as itrelates to cancer anorexia. Based on the previously described crite-ria, all but one of the 13 reports that assessed affective-like behav-ior found significant increases in depressive-like behavior in abroad range of solid tumor models and one leukemia model rela-tive to tumor-free controls (Table 1). Therefore, it appears thatvarying tumor types and induction methods produce similaraffective-like consequences, though more studies would be neces-sary to determine if model type influences behavioral outcomes.One of the standardized tests validated to assess depressive-likebehavior (Krishnan and Nestler, 2008) is a tail suspension test inwhich mice are suspended by their tail and the latency and dura-tion of immobility (versus active struggling) is quantified over a5-min period. Immobility behavior in this context is hypothesizedto be analogous to clinical symptoms of despair. As evidence of thistest’s predictive validity, pharmacological treatment with antide-pressants for several weeks prior to testing ameliorates the immo-bility behaviors. For example, mice that are subcutaneouslyinoculated with murine hepatoma cells display significantincreases in immobility duration using the tail suspension test12 days after inoculation, a behavioral change that is not observedearlier (6 or 8 days after inoculation), when tumor size is relativelysmall (Qi et al., 2009). Other reported increases in depressive-likebehaviors in tumor-bearing rodents include what is termed‘‘behavioral despair’’ using the Porsolt forced swim test and reducedpreference for sucrose-infused drinking water (i.e., sucrose anhe-donia). In rodents, the absence of preferential consumption ofsucrose solutions over tap water is hypothesized to be homologousto symptoms of anhedonia in depressed patients. Tumor-bearinganimals consistently display reductions in sucrose preference(DeWys, 1974; Godbout et al., 2005; Lamkin et al., 2011; Pyteret al., 2009; Smith et al., 1994; Xiu et al., 2010), which do notappear to be driven by changes in nutritional motivation norchanges in taste thresholds, as preference for a saccharine solution(non-nutritive) is also reduced and aversion to noxious solutions(e.g., quinine, hydrochloric acid) remains unchanged (Smith et al.,1994).

In addition to being a measure of fatigue, total locomotor activ-ity in an open field also assesses whether hyperactivity, a hypoth-esized indicator of anxiety-like behavior, is manifest intumor-bearing models. In contrast, hypoactivity (i.e., lethargy) isnoted in several tumor models (Table 1). An arguably moreanxiety-specific measure gleaned from the same open field para-digm is central tendency, the conflict between rodents’ explorationof the bright, exposed center of the open field versus remaining inclose proximity to the relatively protected, dark edges of the field(Crawley, 2006). Central tendency is not affected by the presenceof mammary tumors in rats (Pyter et al., 2009). A similarlight-dark conflict is presented using the elevated plus maze testfor anxiety-like behavior, and the results in tumor-bearing rodentsindicate that there is no apparent deficit in this behavior either(Pyter et al., 2009; Walf and Frye, 2010). In contrast,obsessive-compulsive anxiety-like behavior is significantly ele-vated in tumor-bearing rats (Pyter et al., 2009). Finally, one studyindicates that behavioral responses of tumor-bearing mice to asocial defeat paradigm, in which a highly aggressive conspecific

interacts with the tumor-bearing subject, are characterized byincreased avoidance of social interactions and decreasednon-social exploration (Vegas et al., 2004). The authors argue thatthese behaviors may be consistent with avoidance behaviors,which are typical symptoms of depressed individuals.

Cognition is primarily assessed through tests of learning andmemory in non-human animals. Four out of seven of the reportsincluded in the present search focus on learned taste aversion inthe context of cancer-associated anorexia and cachexia. By manip-ulating the type of chow that was administered throughout thetumor induction and growth paradigm, these studies inadvertentlyexamined the effects of tumors on classical conditioning. Ratsimplanted with sarcoma, leydig cell, or mammary tumors success-fully develop a learned taste aversion to novel diets (conditionedstimulus) eaten during tumor growth (unconditioned stimulus)(Bernstein and Sigmundi, 1980; Bernstein, 1985; Treneer andBernstein, 1987); but see one experiment using mammary tumors(Bernstein and Fenner, 1983). Extinction of this taste aversion (i.e.,the learned acquisition of a new relationship between the sametwo stimuli), at least 25 days after the tumor is removed, however,is impaired relative to both tumor-free controls on the same dietscheme and tumor-bearing controls that receive a novel (andtherefore, preferred) diet post-tumor excision (Bernstein, 1985;Treneer and Bernstein, 1987). This suggests that: (1) althoughthe pairing of the conditioned and unconditioned stimuli is longerin duration and less intense than other classical conditioning para-digms, the aversions developed are quite robust, and (2) the resis-tance to extinction in rats that previously had tumors may reflectan impairment in reversal learning. Finally, in advanced stages ofboth mammary and leydig cell tumor progression, the learnedtaste aversion spontaneously dissipates, indicating that the tasteaversion memory may become impaired or disrupted over pro-longed or advanced stages of tumor development (Bernstein,1985).

The remaining studies on cognitive function in tumor-bearingmodels examined other modalities of learning and memory usinga variety of standardized behavioral tests. For example, the abilityto distinguish between novel and familiar objects is remarkablyimpaired in tumor-bearing rats and mice (Pyter et al., 2010; Yanget al., 2014). Using a fear-based classical conditioning paradigm,tumor-bearing rats and mice tend to display modest impairmentsin passive auditory conditioning (Pyter et al., 2010), but not in con-textual conditioning (Pyter et al., 2010; Yang et al., 2012). In termsof hippocampal-based learning, rats with tumors make morelong-term, reference memory errors in an appetitive radial armmaze task, while working memory remains similar to tumor-freecontrols. Long-term memory in an aversive water maze test isunchanged by the presence of a tumor (Pyter et al., 2010).

2.3. Neuroinflammatory correlates of sickness, affective-like, andcognitive impairment behaviors in tumor-bearing rodent models

The evidence for the direct involvement of inflammatorycytokines (IL-1, IL-6, TNFa, INF-c) in the induction of the somaticbehaviors of anorexia/cachexia is quite prevalent (for reviews seeDianliang, 2009; Matthys and Billiau, 1997; Plata-Salamán, 2000;Tisdale, 2002). Given the high likelihood of mechanistic overlap,much may be gained by assimilating the previously discreet olderliterature on metabolism and the more recent affective/cognitiveresearch in cancer models.

From the metabolic work, it is evident that many cancercachexia models display elevated proinflammatory cytokine andcytokine receptor proteins and transcripts in the whole brain(Catalano et al., 2003), within brain regions known to regulateaffective-like and cognitive behaviors (e.g., hippocampus, hypotha-lamus, cortex, brainstem, cerebellum; Chance et al., 2003;

Table 1Affective-like and cognitive behavioral and inflammatory consequences of peripheral tumor growth in rodents.

PublicationFirst Author(Year)

Tumor model Behavioral tests Putative behavioral correlate Peripheralinflammatorymeasures

Centralinflammatorymeasures

Yang et al.(2012)

Mouse breast (SI; sc) Tail suspension Depressive-like behavior (learnedhelplessness/behavioral despair)

Hippocampal COX-2 and iNOS expression

Yang et al.(2014)

Mouse colorectal(SI; sc)

Tail suspension Depressive-like behavior (learnedhelplessness/behavioral despair)

Blood IL-6 Hippocampal IL-6 and TNFa mRNA

Cell proliferation and neurogenesis markersand qualitatively shorter dendrites in dentategyrusHippocampal BDNF and COX-2 mRNA

Fang et al.(2012)



Blood IL-12(initially)

Binding ratio of 123I-ADAM in various SERT-richin relevant brain regions

Qi et al. (2009) Mouse hepatoma(SI; ip)

Tail suspension Depressive-like behavior(learned helplessness/behavioraldespair)

Whole brain SOD activity (reversible byfluoxetine)

Hippocampal GMFb and BDNF mRNA(reversible by fluoxetine)

Norden et al.(2015)



Blood IL-6 Cortical microglial activation (reversible byminocycline

Sucroseanhedonia

Depressive-like behavior(anhedonia)

Hippocampal and cortical IL-1b and IL-6(reversible by minocycline)

DeWys (1974) Rat breast (SI; sc) Sucroseanhedonia


Lamkin et al.(2011)

Mouse ovarian (SI; ip) Sucroseanhedonia


Blood IL-6,TNFa, IL-10

Xiu et al.(2010)

Rat breast (SI; sc) Sucroseanhedonia


Smith et al.(1994)

Rat sarcoma (implant;sc)

Sucrose/saccharineanhedonia


Pyter et al.(2009)

Rat breast (carcinogen) Porsolt forcedswim

Depressive-like behavior(learned helplessness/behavioraldespair)

Tumor IL-1band GM-CSFmRNA

Hippocampal IL-1b, IL-6, TNFa, and IL-10

Sucroseanhedonia


Papiez et al.(2009)

Rat myeloid leukemia(SI; ip)

Porsolt forcedswim

Depressive-like behavior (learnedhelplessness/behavioral despair)

Cortical and hippocampal antioxident potential

Cortical and hippocampal lipid peroxidation,mRNA response to oxidative stress challengeCortical and hippocampal SOD activity (butinitial decrease in hippocampus)Cortical 5-HT2a density and binding affinity ofb-adrenergic receptors

Lebeña et al.(2014)

Mouse melanoma(SI; iv)

Tail suspension Depressive-like behavior(learned helplessness/behavioraldespair)

Blood IL-6 forlarge tumors

Hippocampal IL-6 and TNFa mRNA

Striatal DOPAC, DA, 5-HT; prefrontal 5-HIAA,5-HIAA/5-HT

Vegas et al.(2004)


Social defeat Potentially depressive-likebehavior (social avoidance)

Hypothalamic 5-HT

Hypothalamic 5-HIAA/5-HT ratio

Vegas et al.(2004)


Social defeat Anxiety-like behavior(exploration)

Hypothalamic 5-HT

Hypothalamic 5-HIAA/5-HT ratio

(continued on next page)

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Table 1 (continued)

PublicationFirst Author(Year)

Tumor model Behavioral tests Putative behavioral correlate Peripheralinflammatorymeasures

Centralinflammatorymeasures

Pyter et al.(2009)

Rat breast (carcinogen) Marble burying Anxiety-like behavior(obsessive-compulsive)

Tumor IL-1band GM-CSFmRNA

Hippocampal IL-1b, IL-6, TNFa, and IL-10

Qi et al. (2009) Mouse hepatoma(SI; ip)

Total locomotoractivity

Sickness behavior (lethargy) Anxiety-likebehavior(hyperactivity)

Whole brain SOD activity (reversible byfluoxetine)

Hippocampal GMFb and BDNF mRNA(reversible by fluoxetine)

Fang et al.(2012)




Blood IL-12(initially)

Binding ratio of 123I-ADAM in various SERT-richin relevant brain regions

Xiu et al.(2010)

Rat breast (SI; sc) Total locomotoractivity


Lamkin et al.(2011)

Mouse ovarian (SI; ip) Total locomotoractivity


Blood IL-6,TNFa, IL-10

Papiez et al.(2009)

Rat myeloid leukemia(SI; ip)



Cortical and hippocampal antioxident potential

Cortical and hippocampal lipid peroxidation,mRNA response to oxidative stress challengeCortical and hippocampal SOD activity (butinitial decrease in hippocampus)Cortical 5-HT2a denstity and binding affinity ofb-adrenergic receptors

Yang et al.(2014)


Novel objectrecognition

Cognition (temporal lobe-dependent learning andmemory)

Hippocampal IL-6 and TNFa mRNA

Cell proliferation and neurogenesis markersand qualitatively shorter dendrites in dentategyrusHippocampal BDNF and COX-2 mRNA

Pyter et al.(2010)

Rat breast (carcinogen) Radial arm maze Cognition (hippocampal-dependent learning and memory– aversive)

Hippocampal IL-1b mRNA

Novel objectrecognition

Cognition (temporal lobe-dependent learning andmemory)

Bernstein(1985)

Rat leydig cell andbreast (both implant;sc)

Taste aversion (inadvanced disease)

Cognition (classical conditioning with tumor asunconditioned stimulus)

Treneer andBernstein(1987)

Rat leydig cell (implant;sc) and tumor resection

Taste aversion(reversallearning)

Cognition (classical conditioning with tumor asunconditioned stimulus)

Bernstein andSigmundi(1980)

Rat sarcoma (implant;sc)

Taste aversion Cognition (classical conditioning with tumor asunconditioned stimulus)

Bernstein andFenner(1983)

Rat leydig cell (implant;sc)

Taste aversion Cognition (classical conditioning with tumor asunconditioned stimulus)

N/C = no change, SI = syngeneic inoculation, sc = subcutaneous, iv = intravenous, ip = intraperitoneal, OVX = ovariectomized.

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Plata-Salamán, 2000; Turrin et al., 2004; Wang et al., 2001), andeven in CSF (Opara et al., 2005) relative to pair-fed tumor-free con-trols or simply tumor-free controls. The null-finding exceptions arerare (Carson et al., 1998; Wang et al., 2001). Mounting evidenceindicates that this central cytokine production is tumor-initiatedrather than host-derived (Baltgalvis et al., 2010; Cahlin et al.,2000; Kawamura et al., 1999; Rebeca et al., 2008). Notably, evi-dence of elevations in circulating cytokines need not be presentfor tumor-induced inflammation to be transduced into brain cyto-kine production (Quan, 2014). In cancer models of depressive-likebehavior and select cognitive impairments, elevations in brainproinflammatory cytokine production are observed primarily inthe cortex and hippocampus (Norden et al., 2015; Pyter et al.,2010; Pyter et al., 2014; Pyter et al., 2009; Yang et al., 2014).

Local brain cytokine production, in turn, can influence a numberof neural pathways by which tumors may induce behavioralchanges (Plata-Salamán, 2000; Tisdale, 2002). Those known to over-lap with the hypothesized mechanisms underlyingcytokine-induced affective, somatic and cognitive behavior involve:iNOS and COX enzymatic activities, neuronal death, and tryptophanmetabolism. Briefly, the negative behavioral consequences oftumors are associated with elevations in iNOS expression amongvarious hypothalamic regions (Wang et al., 2001; Yang et al.,2012) and elevations in cerebral blood vessel expression of COX-1(Ruud et al., 2013; not COX-2 (Wang et al., 2001). The results frommeasuring constitutive hippocampal COX-2 expression intumor-bearing models with affective-like behavior or cognitiveimpairment are mixed (Yang et al., 2012, 2014). Evidence of micro-glial activation has also been detected in the hippocampus and cor-tex of tumor-bearing rodents (Norden et al., 2015; Pyter et al., 2014;but see Yang et al., 2012). Many of these elevations in neuroinflam-matory markers are attenuated by the systemic administration ofthe anti-inflammatory agent, minocycline (Norden et al., 2015).Furthermore, adding a peripheral inflammatory challenge (i.p. LPSinjection) to a rat model of mammary cancer exacerbates the neu-roinflammatory signaling responses of IL-1b, IDO, and markers ofNF-jB and microglial cell activation among various brain regionsthat regulate affective-like and cognitive behavior (Pyter et al.,2014). These results suggest that both baseline neuroinflammationand neuroinflammatory responses are altered by the presence of aperipheral tumor.

Peripheral tumors associated with poor novel object recognitionalso reduce cell proliferation, neurogenesis, and dendritic length(qualitatively) in the dentate gyrus of the hippocampus (Yanget al., 2014, but see Yang et al., 2012). Growth factors associatedwith neurogenesis, GMFb and BDNF, are reduced or remain unal-tered in the hippocampus in tumor-bearing rodents that displaycognitive impairments or depressive-like behavior (Qi et al.,2009; Pyter et al 2010; Yang et al 2014) Neural redox homeostasismay underlie these changes in brain plasticity as reduced oxidasepotential is detected in brains of tumor-bearing mice withdepressive-like behavior (Chen et al., 2006; Papiez et al., 2009; Qiet al., 2009), which is reversible with antidepressant treatment(Qi et al., 2009).

Weight loss in a tumor-bearing model is also associated withcerebellar atrophy and reduced numbers and size of Purkinje neu-rons (Michalak et al., 2006), suggesting that neuronal apoptosis inthe cerebellum may be a consequence of peripheral tumor growth.Other pathways downstream of brain cytokine production that areobserved to be modulated in these models of cancer cachexia, butmay be less relevant to affect/cognition, include changes in neu-ronal K+ channel expression (Coma et al., 2003; Vicente et al.,2004) and in metabolic neurohormone synthesis (Chance et al.,2003).

Lastly, altered amino acid production and turnover in the brain,the particularly relevant tryptophan catabolism (reviewed in

Laviano et al., 1996), is reported in rodent cancer models. Braintryptophan concentrations are consistently higher in cachexiatumor-bearing rodents relative to pair-fed, tumor-free controls(Chance et al., 1988; Chance et al., 1983; Krause et al., 1979), evendays prior to gross tumor palpability (Muscaritoli et al., 1996). Thetryptophan metabolite and target of many antidepressant treat-ments, serotonin (5-HT), is also increased in brain tissue oftumor-bearing rodents (Chance et al., 1988, 1983; Muscaritoliet al., 1996), but see (Krause et al., 1979). Slightly different fromthe cachexia literature, however, whole brain 5-HT concentrationsand SERT binding are decreased, whereas indicators of 5-HT turn-over (5-HIAA, 5-HT/5-HIAA ratio; (Vegas et al., 2004) remainunchanged in tumor-bearing mice with depressive-like behavior.This may be counterintuitive given that depressive-like behavioris associated with reduced brain 5-HT concentrations (Müller andSchwarz, 2007). However, (1) 5-HT concentrations do not reflect5-HT release and, (2) turnover (or catabolism) of 5-HT may besimultaneously elevated as demonstrated by the concurrent eleva-tions in brain 5-HT metabolites (e.g., 5-HIAA) and 5-HIAA:5-HTratios (Chance et al., 1988, 1983; Chuluyan et al., 2000; Krauseet al., 1979; Muscaritoli et al., 1996; Uomoto et al., 1998). Tumorresection resolves many of these alterations in brain amine con-centrations (Chance et al., 1988). Future determination of the activ-ity of the kynurenine pathway downstream from tryptophan intumor-bearing models is necessary to elucidate the details of thesepotential neurotransmitter mechanisms.

Arguably most consistent with data attainable in humans, a cou-ple of studies have linked elevated circulating cytokines and sick-ness behavior in these rodent models. For example, significantnegative correlations were found between blood IL-6 concentrationsand voluntary wheel running, cachexia (Wood et al., 2006), and loco-motion (Lamkin et al., 2011). Circulating tryptophan or relevanttryptophan ratios (to 5-HT metabolites) are also altered in canceranorexia models (Chance et al., 1988, 1983; Krause et al., 1979;Meguid et al. 1998; Muscaritoli et al., 1996) and are significantly cor-related with the onset of a palpable tumor (Källberg et al., 2010) andthe reduction in food intake (Muscaritoli et al., 1996).

3. Cancer patients prior to treatment

A separate line of inquiry concerns cancer patients prior to treat-ment (i.e., prior to surgical resection of tumor, chemotherapy, radi-ation). Pre-treatment data provides important insights into bothbiological consequences of tumor development and attendant psy-chological and behavioral symptoms. For this review, we focus pri-marily on English language original reports indexed in Pubmedthat considered inflammatory factors and/or psychological andbehavioral symptoms in cancer patients prior to treatment. Searchterms included: ‘‘depression,’’ or ‘‘anxiety,’’ or ‘‘cognition,’’ or ‘‘neu-ropsychological test,’’ or ‘‘cancer,’’ or ‘‘tumor,’’ indexed from ‘‘nodetermined start date’’ to January, 2015. Studies that only examinedthese factors in patients during or following treatment were notincluded. For psychological and behavioral factors, we focused pri-marily on research that consider symptoms prior to diagnosis, asthe diagnosis itself represents a major psychosocial stressor capableof inducing both depressive and immune consequences. For studiesof cognitive impairment in cancer patients prior to treatment wefocused on studies that assessed multiple cognitive domains and,due to the small number of available studies, included studies inwhich patients were post-surgery but pre-chemotherapy/radiationin addition to studies of patients prior to all treatment.

3.1. Inflammation in cancer patients prior to treatment

Similar to in rodent cancer models, tumor-derived inflamma-tion in humans originates from tumor cells, the surrounding


stromal cells (Gogusev et al., 1993; Kinoshita et al., 1999; Offneret al., 1995; Pusztai et al., 1994; Watson et al., 1990) ortumor-associated macrophages (TAMS), and infiltrating T-cells(Allavena et al., 2008a; Allavena et al., 2008b). Circulatingpro-inflammatory cytokines are elevated in various cancer popula-tions prior to any treatment including ovarian cancer (Lutgendorfet al., 2008), colorectal cancer (Belluco et al., 2000), lung cancer(Wojciechowska-Lacka et al., 1996), breast cancer (Benoy et al.,2002), pancreatic cancer (Okada et al., 1998), gastric cancer (Kimet al., 2003), prostate cancer (Michalaki et al., 2004), head and neckcancer (Riedel et al., 2005), renal cell carcinoma (Yoshida et al.,2002), and bladder cancer (Mahmoud El-Salahy, 2002). High con-centrations of circulating inflammatory cytokines such as IL-6and TNF-a are associated with later stage disease (Belluco et al.,2000; Kim et al., 2003; Kozłowski et al., 2003; Michalaki et al.,2004; Okada et al., 1998; Yoshida et al., 2002), poorly differenti-ated tumors (Goswami et al., 2013; Kaminska et al., 2005;Ljungberg et al., 1997; Mahmoud El-Salahy, 2002; Yoshida et al.,2002) and tumor size/volume (Chung and Chang, 2003;Kaminska et al., 2005; Plante et al., 1994) in a variety of malignan-cies. Elevations of circulating pro-inflammatory cytokines havealso been associated with less common indices of disease severityincluding extent of tumor necrosis in colorectal cancer (Guthrieet al., 2013; Richards et al., 2012). Spontaneous release ofpro-inflammatory cytokines in cultures of primary tumor furthersuggests that circulating levels of inflammatory molecules are atleast partially tumor-derived in some malignancies (Burger et al.,1995; Toutirais et al., 2003; Wigmore et al., 2002). Inflammatorycytokines are also elevated in ascites fluid proximal to the tumorin ovarian cancer patients (Moradi et al., 1993) and malignantpleural effusions in lung cancer (Yamaguchi, 2000). In ovarian can-cer, levels of IL-6 from ascites are strongly associated with IL-6 inplasma; (Costanzo et al., 2005), similar to that of malignant pleuraleffusions from lung cancer patients (Yamaguchi, 2000). Other sys-temic effects of tumor-associated inflammation have been noted,especially alteration of the hypothalamic–pituitary–adrenal(HPA) axis. Altered cortisol patterns have been identified in ovariancancer patients (Weinrib et al., 2010), endometrial cancer patients(Sannes et al., 2013), and oral cancer patients (Bernabé et al., 2012)prior to treatment. In ovarian cancer patients, these patterns aresignificantly associated with IL-6 concentrations in the ascites fluid(Schrepf et al., 2015) and in plasma (Lutgendorf et al., 2008).

In addition to pro-inflammatory cytokines, cancer patients priorto treatment show altered patterns of tryptophan metabolism. IDOactivity is associated with tumor induction and is often highlyexpressed in solid tumors (Munn and Mellor, 2013). Higherkynurenine/tryptophan ratios and lower tryptophan concentra-tions in blood compared to healthy controls have been reportedin colorectal cancer, malignant melanoma, non-small cell andsmall cell lung cancer, ovarian cancer, endometrial cancer, vulvarcancer, and breast cancer patients (de Jong et al., 2011; Enginet al., 2010; Huang et al., 2002; Lyon et al., 2011;Sperner-Unterweger et al., 2011; Suzuki et al., 2010; Weinlichet al., 2007), although the opposite pattern was noted in a studyof primary cervical cancer patients (Fotopoulou et al., 2011).Thus, it appears that increased IDO activity in peripheral blood isassociated with many malignancies prior to treatment.

3.2. Affective/somatic symptoms of depression and cognitiveimpairment in cancer patients prior to treatment

Whether a clinical diagnosis of depression is associated withsubsequent increased incidence of cancer in the following yearsremains a controversial subject (Oerlemans et al., 2007).However, for some malignancies, changes in affect and somaticsymptoms are noted in the months prior to and at the time of a

diagnosis of cancer, consistent with the time frame of tumor devel-opment. This review will focus on these symptoms.

In pancreatic cancer, there is strong evidence that affectivesymptoms of depression may manifest prior to diagnosis (Greenand Austin, 1993; Joffe et al., 1986; Sebti et al., 2014). One studyreported that clinically relevant depression occurs in 50% ofpatients in the year prior to diagnosis (Joffe et al., 1986). Amongcommonly reported symptoms in pancreatic cancer patients priorto diagnosis, affective symptoms like crying spells and feelings ofhopelessness were common in addition to somatic symptoms likeloss of appetite, fatigue, anorexia, and insomnia (Green and Austin,1993).

Symptoms that precede a diagnosis of ovarian cancer overlapconsiderably with somatic symptoms of depression. Case controlstudies using retrospective recall of symptoms report that fatigue(O.R. 3.9, 95% CI 2.5–6.1), weight loss or weight gain (OR 14.2,95% CI 8.2–24.5), and loss of appetite (OR 8.8, 95% CI 4.3–18.2)are much more commonly reported by ovarian cancer patientsprior to diagnosis than controls visiting the same clinics (Olson,2001; Vine et al., 2003). Fatigue and weight loss/gain are also morecommon amongst those with advanced (stages III–IV) versus early(stages I–II) of ovarian cancer. The onset of these symptoms wasmost often reported as 2–7 months prior to diagnosis, suggestingthat they are not part of pre-existing condition, but rather are con-sistent with the timeframe of tumor development. Another studyexamining medical records (and hence free of recall bias) foundthat loss of appetite, fatigue and anxiety are all significantly morecommon in ovarian cancer patients compared to controls in the6 months preceding diagnosis (Friedman et al., 2005).

In a retrospective study of symptoms prior to lung cancer diag-nosis, most symptoms were reported as occurring in the12 months prior to diagnosis, and included 68% of patients report-ing fatigue, 64% change in appetite, 59% changes in sleep, and 50%weight loss (Corner et al., 2005). These results were confirmed by acase-control analysis of symptoms recorded in primary care set-tings in the two years prior to a lung cancer diagnosis that foundfatigue, loss of appetite, and loss of weight are more commonlyreported by patients than controls (fatigue OR 2.3, 95% CI 1.9–2.9; loss of appetite OR 4.8, 95% CI 3.3–7.0; loss of weight OR 6.2,95% CI 4.5–8.6; Hamilton et al., 2005). Importantly, when the final180 days prior to diagnosis were excluded from the analyses fati-gue, loss of appetite, and loss of weight no longer distinguish casesfrom controls. This suggests that these symptoms manifest rela-tively close to the time of diagnosis.

In women awaiting surgery for suspected ovarian cancer, symp-toms of somatic and affective depression are more prevalent inthose subsequently diagnosed with ovarian cancer than in thosewith tumors of low malignant potential, despite facing presumablysimilar levels of distress and no differences in levels of interper-sonal difficulties (Lutgendorf et al., 2008). Nonetheless, it is possi-ble that symptoms of invasive disease (e.g. bowel distension) mayhave contributed to suspicion of ovarian cancer and consequentsymptoms of depression, though this possibility warrant furtherinvestigation. One study of women presenting at an outpatientclinic subsequently diagnosed with breast cancer found that 28%met criteria for state anxiety and depression prior to diagnosisthough the prevalence of these affective disturbances were notreported for women who were subsequently found to be free ofcancer (Van Esch et al., 2012). In contrast, another report usingassessment of affective symptoms in women prior to diagnosiseither with breast cancer or benign disease found that neither anx-iety nor depression were higher in cancer patients than womenwith benign disease in the two years prior (Eskelinen andOllonen, 2011). Similarly, another study that examined physicaland mental well-being in the year before a prostate cancer diagno-sis found no differences between men that were subsequently


diagnosed with prostate cancer and matched healthy controls(Reeve et al., 2012). Therefore, increased symptoms of depression,and specifically affective symptoms, are not universal prodromalfeatures of cancer.

That somatic symptoms may be more pronounced in cancerpatients prior to treatment is unsurprising. In a large-scale mixedcancer population (n = 213) post-diagnosis but pre-treatmentsomatic symptoms are responsible for most of the variance inBeck’s Depression Inventory scores when compared to healthycontrols (Wedding et al., 2007). More specifically, the effect sizes(Cohen’s D) for the difference in affective symptoms averaged0.12 between cancer patients and controls versus 0.34 for somaticitems. Interestingly, some affective items are considerably less pro-nounced in cancer patients (i.e. sense of failure, d = �2.35, guilt,d = �1.00), while every somatic item except loss of libido is moreprevalent in cancer patients. Comparing patients with solid tumorsto those with haematological malignancies reveals no differencesin affective items or total depression scores, but significantlyhigher somatic scores in patients with solid tumors (Weddinget al., 2007).

A relatively small number of published studies have examinedneuropsychological test performance in cancer patients prior totreatment. Eleven total studies were identified: 5 in breast cancersamples (Ahles et al., 2008; Hermelink et al., 2007; Hurria et al.,2006; Mandelblatt et al, 2014; Wefel et al., 2004), and 1 each insamples of prostate cancer (Green et al., 2004), ovarian cancer(Mayerhofer et al., 2000), testicular cancer (Wefel et al., 2011),head and neck cancer (Bond et al., 2012), lung cancer (Meyerset al., 1995), and leukemia (Meyers et al., 2005). Of these, five werein samples prior to the receipt of any treatment and five were sam-ples in which some patients had completed surgery but notchemotherapy or radiation. Sample sizes ranged between 18 and110 participants.

Reviewing the areas of cognitive impairment tested across stud-ies resulted in enough crossover in several domains by percent ofsample impaired to warrant comparison across studies: globalimpairment (6 studies), verbal learning – both total recall (5 stud-ies) and delayed recall (4 studies), manual dexterity (4 studies),executive function (5 studies), visual scanning (5 studies), verbalfluency (5 studies), processing speed (4 studies) and auditoryattention (3 studies) (Table 2). Some studies that did not reportpercentages of impaired patients are discussed but could not con-tribute to mean and median calculations. Mean and median per-centages of cognitive impairment in cancer patients acrossstudies were as follows: global impairment, 32% (median 33%);total verbal learning 31.7% (median 37.7%); delayed recall 39.3%(median 33%); executive functioning 23.3% (median 22%); manualdexterity 24.5% (median 24.5%); visual scanning 18.9% (median16%); verbal fluency 10.6% (median 10%); processing speed 7.8%(median 6.2%); auditory attention 5.4% (median 5%). Several stud-ies also compared cancer patients prior to treatment to controls ornormative means using group means rather than percentage ofsample impaired, and these generally revealed fewer differences.

These results reveal a broadly consistent pattern of impairment.Approximately one-third of patients demonstrated impairment intotal recall and delayed recall on verbal learning tasks, andone-quarter demonstrated impairment on manual dexterity andexecutive functioning tasks. Approximately 20% demonstratedimpairment on visual scanning tasks, while approximately 10% orfewer were impaired on verbal fluency, processing speed, andauditory attention tasks. The percentages of impaired patient inthe verbal learning, executive function, manual dexterity, andvisual scanning domains were considerably higher than whatwould be expected were the samples drawn from a healthy popu-lation, while verbal fluency, processing speed and auditory atten-tion did not appear to differ substantially from normative

expectations. Verbal learning (either total recall or delayed recall)was the most impaired domain in every study in which it wasassessed, while processing speed and auditory attention were theleast impaired domains in all but one study.

Methodological differences appeared to play a large role in thedifferential findings. For instance, studies which examined samplemeans in comparison to healthy controls or normative meansappeared to find fewer differences than studies which determinedif individual participants met criteria for impairment. For instance,one 2007 study of breast cancer patients found no significant dif-ference in verbal learning using group means compared to norma-tive means (Hermelink et al., 2007) while a 2004 study of breastcancer patients using individual scores compared to normativemeans found that the number of patients impaired on verbal learn-ing tasks was twice what would be expected in a normal, healthypopulation (Wefel et al., 2004). As it would appear that many ofthe sample means studied would fall within a normal performancerange according to normative means, group means likely maskindividuals with impaired performance. This further suggests thatcognitive impairment affects a particular, vulnerable subsample ofcancer patients prior to treatment.

Studies that consider moderating factors reveal inconsistentresults. For instance, 3 of 4 studies that considered fatigue as amoderating factor did not find it to be associated with any testresults, while the fourth found it to be associated only with pro-cessing speed and global impairment. Similarly, depression wasnot related to neuropsychological test results in three of five stud-ies, but was associated with processing speed in two studies andboth verbal learning and global impairment in another. In onestudy of breast cancer, medical comorbidities were the only factorassociated with worse neurocognitive performance, such that hav-ing 2 or more comorbidities was associated with a nearly 9 foldincrease in the risk for cognitive impairment (Mandelblatt et al.,2014).

3.3. Inflammatory correlates of somatic/ affective symptoms ofdepression and cognitive impairment

Elevations in peripheral markers of inflammation are linked tothe elevations in somatic and affective symptoms in cancerpatients prior to treatment in a variety of malignancies. In ovariancancer patients with invasive disease, elevated IL-6 in plasma andascites is associated with greater somatic, but not affective, symp-toms of depression prior to diagnosis (Lutgendorf et al., 2008). Inbreast cancer patients prior to the receipt of treatment, a diagnosisof depression by structured interview (Structured ClinicalInterview for DSM-IV, SCID) is associated with both elevatedplasma IL-6 and abnormal dexamethasone suppression tests com-pared to non-depressed patients (Soygur et al., 2007). Similarly,levels of soluble IL-6 receptor (sIL-6r) and CRP are positively asso-ciated with fatigue and affective symptoms of depression in breastcancer patients prior to treatment (Courtier et al., 2013; Pertl et al.,2013). In patients with peritoneal carcinomas, serum levels of IL-6and CRP are associated with greater fatigue and somatic symptomsof depression, but not affective symptoms (Low et al., 2014). Inprostate cancer patients with non-metastatic disease elevatedTNF-a levels in serum are associated with fatigue, depressionand anxiety (HADS) (Dirksen et al., 2013). In malignant melanomapatients, sIL6-r levels in serum are negatively associated withself-reported combined affective and somatic symptoms(Self-Reported Depression Scale; SDS) and sTNF-r levels positivelyassociated (Friebe et al., 2007) In metastatic colorectal cancerpatients serum IL-6 levels are positively associated with loss ofappetite and nausea/vomiting, TGF-b levels are positively associ-ated with loss of appetite and fatigue (Rich et al., 2005). Inadvanced lung cancer patients higher Glasgow Prognostic Scores

Table 2Study characteristics and results of neuropsychological tests in cancer patients prior to chemotherapy/radiation.

First author (year) Ahles et al. (2008) Bond et al. (2012) Green et al. (2004) Hermelink et al. (2007) Hurria et al. (2006)

Sample Breast cancer Head and neck cancer Prostate cancer Breast cancer Breast cancerTime Post-surgery/pre-chemotherapy/radiation Pre-treatment Pre-treatment Pre-treatment Post-surgery/pre-chemotherapy/radiationInclusion criteria Stage 1–3A, 18–70 years 21 or older Non-localized prostate cancer Non-metastatic breast cancer Newly diagnosed stage 1-3 breast cancer, age 65

or olderExclusion criteria CNS disease, previous cancer/cancer treatment, neurologic

disorder, substance abuse, brain injury, psychiatric disorderBrain metastases, intracranialradiation, previous cancer

Previous hormonal therapy, severeLUTS, abnormal serum testosterone

None listed Metastatic disease, psychiatric disorder, previouscancer treatment

n 110 70 77 109 31Definition of Global

impairment2 domains below 1.5 S.D. of healthy controls, or 1 domain 2.0S.D. belowa

Average global deficit score P0.5 N/A 65% normative mean on 2 or moredomains

2 domains below 2.0 S.D. below normativemeans

Global impairment 22% 47% N/A 31% 11%Definition of

impairment onindividual tests

Below 1.5 S.D. of healthy controlsa T-score <40 by normative means Comparison to healthy control Mean comparison to HC N/A

Verbal learning N/A 25% <Healthy controls Not different from norms N/ATest N/A RAVLT total N/A N/ADelayed recall N/A 21% N/A N/A N/ATest N/A RAVLR DR N/A N/A N/AAuditory attention N/A N/A N/A Not different from norms N/ATest N/A N/A N/A Digit span N/AProcessing speed N/A 19% <Healthy controls >Norms N/ATest N/A SDMT N/A N/A N/AExecutive N/A 22% Marginal < healthy controls <Norms N/ATest N/A TMT-B Stoop inhibitory TMT-B N/AVerbal fluency N/A 17% N/A <Norms N/ATest N/A AVF N/A RWT N/AVisual scanning N/A 16% N/A Not different from norms N/ATest N/A TMT-a N/A TMT-A N/ADexterity N/A N/A N/A N/A N/ATest N/A N/A N/A N/A N/A

First author (year) Mayerhofer et al. (2000) Meyers et al. (2005) Meyers et al. (1995) Wefel et al. (2011) Wefel et al. (2004)

Sample Epithelial ovarian cancer Myelogenous leukemia/myelodysplastic syndrome (AML/MDS)

Small cell lung cancer Nonseminomatous germ cell tumors(NSGCT)of the testis

Breast cancer

Time Pre-treatment Pre-treatment Pre-treatment Post-surgery/pre-chemotherapy 50% pre-surgery, all pre-chemotherapy/radiationInclusion criteria Newly diagnosed EOC, normal blood panel Newly diagnosed AML/MDS Newly diagnosed limited sclc, P8th

grade educationNewly diagnosed NSGCT, age 18–50 Breast carcinoma, 18+ years, P8 years of

educationExclusion criteria Neurologic disorder, psychiatric disorder, brain metastases,

substance abuse, cognition altering medicationN/A psychiatric disorder, substance abuse Neurologic illness, brain injury,

psychiatric disorder, brain metastasisevidence of metastases, psychiatric disorder,previous cancer, cognition altering medication

n 28 54 21 69 18–84b

Definition of globalimpairment

N/A N/A N/A 2 domains below 1.5 S.D. of normativemeans, or 1 domain 2.0 S.D. below

2 domains below 1.5 S.D. of normative means, or1 domain 2.0 S.D. below

Global impairment N/A N/A N/A 46% 35%Definition of

impairment onindividual tests

Median values compared to normative means 2 S.D. below normative mean 1.5 S.D. below normative mean 1.5 S.D. below normative mean 1.5 S.D. below normative means

Verbal learning N/A 44% 38% 37.7% 14%Test N/A HVLT VSRT HVLT HVLT, VSRTDelayed recall N/A 41% 70% N/A 25Test N/A HVLT-DR VSRT-DR N/A VSRT-DRAuditory attention N/A 7% 5% 4.3% N/ATest N/A Digit span Digit span Digit span N/AProcessing speed Not different than norms 8% 0% 4.3% N/ATest Alphabet cross-out test Digit symbol Digit symbol Digit symbol N/AExecutive N/A 29% 38% 21.7% 6%Test N/A TMT-B TMT-B TMT-B TMT-BVerbal fluency N/A 17% 10% 2.9% 6%Test N/A COWA COWA COWA COWAVisual scanning N/A 28% 33% 4.3% 13%Test N/A TMT-A TMT-A TMT-A TMT-ADexterity <Norms 37% 31.5% 17.4% 12%Test Fine motoric test Pegboard Pegboard Pegboard Pegboard

a Estimated by Monte Carlo simulation.b Employed a mixed sample ranging in size from 18 to 84 participants.

10A

.Schrepfet

al./Brain,Behavior,andIm

munity

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(a composite measure of abnormal albumin and CRP levels inblood) are correlated with both depression and anxiety levels(HADS) (Giannousi et al., 2012) and serum CRP levels with fatigue(Brown et al., 2005). However, in a study of colorectal cancerpatients, levels of TNF-a and CRP in plasma are not associated withbaseline depressive symptoms (Archer et al., 2012). Similarly, in astudy of depressed versus non-depressed hepatobiliary carcinomapatients, levels of TNF-a and IFN-c in plasma did not differbetween groups (Steel et al., 2007).

IDO activity has also been linked to somatic and depressivesymptoms in cancer patients. Reduced serum tryptophan is associ-ated with more severe somatic symptoms (RSC) but not anxiety ordepression scales in a sample of colorectal cancer patients (Huanget al., 2002). In pancreatic cancer patients, a lower kynurenicacid:tryptophan ratio in serum is associated with worse symptomsof anxiety and depression (Botwinick et al., 2014). Regarding cog-nitive function, only one study has examined inflammatory corre-lates of impairment in cancer patients prior to treatment and foundthat levels of IL-6 were found to be associated with poorer execu-tive functioning and levels of IL-8 were inversely associated withmeasures of memory (Meyers et al., 2005).

4. Conclusions and limitations

Viewed in tandem, the rodent and human literatures suggestthat similar inflammatory mechanisms and behaviors, which wereinitially established with respect to behavioral changes followingacute immune challenges (i.e. sickness behavior, cognitive impair-ment), are also features of chronic disease (i.e., cancer). Differencesbetween cancer-associated behavioral changes and acute sicknessbehavior are likely due to differing time scales, the magnitude ofinflammation, and subtle differences in underlying mechanisms.One possibility is that tumor growth, in early stages, represents aslow-priming effect on the immune system rather than full activa-tion of conserved sickness responses. In fact, mounting a full sick-ness response over the span of tumor growth would not be viablegiven the high energetic cost of such behaviors (fever, anorexia).The sensitized neuroinflammatory responses to LPS administrationin tumor-bearing rats (Pyter et al., 2014) and microglial activation(Norden et al., 2015; Pyter et al., 2014) support this priminghypothesis.

Significant gaps in knowledge remain. Sleep dysregulation isclearly prevalent in human cancer patients prior to treatment,but little information is known about sleep and associated mecha-nisms in tumor-bearing rodents. While models of tumor-bearingrodents suggest that some anxiety-like behaviors may beenhanced, little is known about symptoms of anxiety and inflam-mation in human cancer patients prior to diagnosis.Methodological disparities have thus far limited inference frombehavioral results in tumor-bearing rodents. For instance, modelswhich clearly result in reduced locomotion are not ideal for behav-ioral tests that required considerable movement such as thetail-suspension and Porsolt forced swim test. Similarly, modelswhich result in wasting and anorexia are not ideal for behavioraltests predicated on food/consumption rewards. Additionally,inflammatory correlates of cognitive impairment have not beenestablished in cancer patients prior to treatment. In other clinicalpopulations, elevated peripheral biomarkers of inflammation(CRP, IL-6) have been associated with neurocognitive decline suchas delayed verbal learning tasks (Bettcher et al., 2012;Grassi-Oliveira et al., 2011; Hudetz et al., 2011) and impaired exec-utive functioning (Hoshi et al., 2010; Mooijaart et al., 2013).Increased markers of indoleamine-2,3-dioxygenase activity inperipheral blood have been linked to poorer global cognitive per-formance in stroke survivors and cardiac patients following

surgery (Forrest et al., 2011; Gold et al., 2011). Some of theseeffects may be hippocampus-dependent, as damage limited tothe hippocampus has previously been associated with impairedrecognition memory and verbal learning in patients sufferinghypoxia-induced brain damage (Hopkins et al., 1995) and hip-pocampal impairments generally produce worse performance onNOR tests in rodent models, though this relationship continues tobe explored (Antunes and Biala, 2012).

This work has several implications for future research. Theappearance of somatic symptoms in the months prior to a cancerdiagnosis again raises the possibility of early detection for somemalignancies. Against this proposition is the fact that most of thesesymptoms appear to be non-specific and experienced by a wideswath of the population. However, this conclusion is based onthe limited survey of symptoms that are discovered in clinic visits.It is unlikely symptoms of anxiety and depression are widely mon-itored. It is possible, therefore, that somatic, depressive, or cogni-tive symptoms may have utility in combination with physiologicmeasures to contribute algorithmically to characterizinghigh-risk patients.

Measures of depression in cancer patients, even those thatattempt to exclude somatic symptoms, likely capture considerableinfluence of tumor-derived processes in some malignancies. This isan issue that has posed a considerable challenge to researchersinterested in affective disturbances in cancer patients. Whiledepressive symptoms are sometimes modeled as a unitary con-struct, in cancer populations it appears that there are differentialassociations between somatic and affective symptoms of depres-sion and measures of inflammation (Lutgendorf et al., 2008).Many theories of depression and sickness behavior emphasizeputative shared inflammatory mechanisms, however, there is alsoevidence that affective and somatic symptoms do not always occurin tandem in acute and chronic illness, and that specific presenta-tions (e.g., melancholic vs. vegetative depression) may be under-girded by independent, albeit associated, mechanisms (Maeset al., 2012). We would advocate, therefore, the use of measuresor structured interviews that allow both somatic and depressivesymptoms to be measured, rather than measures which aggregateboth or exclude somatic symptoms. In cancer populations bothaffective and somatic symptoms have important and sometimesdivergent associations with quality of life outcomes throughoutthe trajectory of treatment (Reuter et al., 2004; Teng et al., 2014).

The understanding that cancer may fundamentally alter behav-ioral processes prior to any treatment should challenge existingparadigms and lead to changes in rodent models of cancer treat-ment and protocols for observational studies of cancer patients.The physiology and behavior of pre-diagnosis cancer patientsmay already be compromised before the advent of other challengesassociated with cancer and cancer treatment. Fig. 1 represents atimeline of various factors involved in the cancer experience thatmay influence the associated behavioral outcomes. Notably,tumors, cancer-associated stressors, and cancer treatments canindependently influence relevant neuroinflammatory pathwaysover chronological stages of cancer, as well, as their likely synergis-tic/additive biological interactions. Finally, persistent negativebehavioral symptoms in cancer survivors suggest that these neu-roimmunological pathways are likely altered over the long term(Fig. 1D). Many rodent models of cancer treatment-related symp-toms (CTRS) do not employ tumor-bearing animals. Given thatthere is now a substantial body of work suggesting that many ofthe behaviors of interest and associated physiological and CNS pro-cesses of interest to CTRS researchers are altered by the presence oftumors, this modeling approach is no longer adequate. Further, theimmunologic changes secondary to cancer and the immunologicchanges secondary to treatment are not necessarily additive, butmay be interactive. In fact, these interactions have begun to be

Fig. 1. Proposed causes underlying cancer-associated behavioral alterations as they evolve over the cancer process: (A) pre-cancer diagnosis, (B) post-cancer diagnosis,pre-treatment, (C) during cancer treatment, and (D) post-treatment, cancer remission.


explored in the context of fatigue and cognitive complaints inbreast cancer patients (Bower et al., 2014; Bower et al, 2013:Bower, 2007; Ganz et al., 2013). Cancer represents a state ofimmunologic compromise; this is demonstrated potently by thedifferential response to subsequent acute immune challenges(i.e., LPS) seen in tumor-bearing rodents, and by the fact that manyalterations of the immune system (e.g., enhanced production ofpro-inflammatory cytokines) associated with cancer-treatmentsymptoms are the same as those that are clearly altered bytumor-related processes. That tumor bearing rats have anenhanced neuroinflammatory signaling cascade response to LPSchallenge may be an important finding for cancer treatment symp-tom research, as Toll-Like receptor 4, which is responsive to LPS,also responds to damage-associated molecular patterns (DAMPs)that are thought to be more prevalent following some cancer ther-apies (Krysko et al., 2013). It is worth considering that predisposinggenetic factors may increase the risk of both cancer and worsesymptoms associated with the disease and treatment. Studies ofgenetic polymorphisms and symptom profiles in cancer patientspre-treatment may help to identify vulnerable patients. In fact, a

recent investigation of breast cancer patients prior to treatmentrevealed that variations in cytokine genes are associated with sub-syndromal depressive symptoms through the treatment trajectory(Saad et al., 2014).

Moving forward, baseline measurements and monitoring ofimmune processes prior to treatment are an important step inobservational studies of cancer patients at risk for cancer treat-ment symptoms. At least one meta-analysis of cancer treatmentrelated cognitive impairment found no evidence for treatmentassociated impairment in studies which included a baseline mea-surement of cognitive function compared to those that usednon-treatment controls (Anderson-Hanley et al., 2003). The lackof studies considering inflammatory processes and cognitive func-tion in cancer patients is an urgent concern. Future research shouldincorporate in vitro challenges of isolated circulating immune cellsfrom cancer patients prior to treatment in order to provide infor-mation about facets of immune compromise not inferable fromsystemic markers of inflammation. Additionally, there is evidencethat depressive episodes may impact inflammatory pathways, asinflammatory markers are seen to increase with greater numbers


of depressive episodes (Maes et al., 2012). It is possible, therefore,that inflammatory mechanisms associated with cancer-treatmentsymptoms may be altered by tumor-associated inflammation anddepressive episodes triggered by diagnosis prior to the impact oftreatment. Non-cancer controls, particularly those facing the samepre-surgical stress but subsequently found not to have malignantdisease, can provide critical information about the relationshipbetween tumor-associated biological mechanisms and psychologi-cal comorbidities. Well-designed imaging studies may play animportant role in future research, as diffusion tensor imaging tech-niques have been able to identify structural alterations that predictfuture remission of depression following antidepressant treatment(Korgaonkar et al., 2014) and transition to chronic pain (Mansouret al., 2013) suggesting that neural signatures may be an importantand underused marker of vulnerable phenotypes in cancer.Structural (e.g. reduced fractional anisotropy in the hippocampalformation) or functional (e.g. reduced functional connectivity inthe prefrontal cortex) changes in networks associated with execu-tive function and verbal learning are strong candidates. In fact, arecent fMRI study found that pre-treatment dysfunction in execu-tive networks was more strongly associated with post-treatmentfatigue and cognitive dysfunction than receipt of chemotherapyin a longitudinal study of breast cancer patients (Askren et al.,2014). As it would appear that a substantial proportion of cancerpatients pre-treatment suffer from deficits in memory tasks, clini-cians should consider what potential impact this may have oninformation provided to patients at this critical juncture. Patientretention of treatment-related information should be assessed incancer patients prior to treatment to determine if alternativestrategies for communication and retention need to be developed.

Acknowledgments

We thank Anthony Baker for creating Fig. 1. The authors aresupported by Grants CA140933 (S.K.) and CA177325 (A.S.) fromthe National Cancer Institute, and Ohio State Medical Center (L.P.).

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