Cancer cachexia is a particular form of metabolic-energetic abnormality frequently occurring in patients with advanced stages of the disease (Van Cutsem & Arends, 2005). The word ‘cachexia’ is taken from the Greek ‘kakos’ meaning ‘bad’ and ‘hexis’ meaning condition or state (Inui, 1999). While sharing similarities with other hypoenergetic defined states such as anorexia and simple starvation (e.g., dramatic reductions in adipose tissue; immunosuppression), cachexia is characterized uniquely by a progressive, involuntary reduction in lean body tissue which serves as the primary driver in the reduction of overall body weight. It is a complex multifactorial syndrome associated with metabolic abnormalities, anorexia (the uncontrolled lack or loss of appetite for food), early satiety and reduced food intake, edema, fatigue, impaired immune-endocrine function, taste changes, and declining attention span and concentration (Rivadeneira et al., 1998; Mutlu and Mobarhan, 2000; Nitenberg and Raynard, 2000; Fearon, 2001; Tisdale, 2001).
While the putative mechanisms and metabolic-energetic pathways underlying the cachetic phenotype have been and are continuing to be excavated and elucidated, there continues to remain a lack of integration with psychological factors influencing the trajectory and ontogeny of the cachetic state. Of critical importance are psychological conditions which may moderate the cachetic-anorexic state by way of their effects on the neuroendocrinological axe of the central and peripheral nervous system. An examination of these interactive pathways is important as psychological factors may serve to worsen the development and progression of the cachetic state, leading to decreased quality of life and increased mortality among disease patients. It is argued here that a developmental regulatory model may serve to best characterize the interaction of psychological variables on the cachetic-anorexic state.
In order to conceptualize such a model, a background into the metabolic-energetic-immune abnormalities of the cachetic-anorexic state is provided. This is followed by a description of the development of emotional regulation (in the context of attachment) and the cascade of neuroendocrine reactions that maladaptive emotional regulatory patterns set in train. These are then integrated into a developmental regulatory model in which psychological maladaptation or dysregulation leads to a worsening of the cachetic state and its associated symptomatology.
Pathogenesis of Cachexia and Associated Abnormalities of Energetic Regulation
Recent research into the molecular and neuropeptidergic contributions to the development of cachexia has yielded an impressive array of findings. A key role of pro-cachetic cytokines as principal players in the development and progression of cachexia has been identified (cf. Inui, 1999; Argiles, Moore-Carrasco, Fuster, Busquets, and Lopez-Soriano, 2005). For example, key roles of tumor necrosis factor-á (TNF-á), interleukin-6 (IL-6), interferon-ã (IFN-ã), leukemia inhibitory factor (LIF), transforming growth factor-â (TGF-â), and cilliary neurotrophic factor (CNTF) have been suggested as mediators of cachexia.
These cytokines not only directly influence the proteolysis of lean tissue, but they also interact with metabolic neuropeptidergic pathways in the hypothalamus-brainstem network which may influence the homeostatic system of body weight regulation, thus indirectly contributing to the loss of body tissue (predominately lean tissue) through anorectic mechanisms. A further finding has been that there is a hypermetabolic state associated with the cachetic state in which the tumor-bearing host is energetically more inefficient than in the typical non-tumor bearing state.
At first glance, this finding is paradoxical given that the normative physiological response to hypoenergetic states (starvation) is a decrease in resting or basal energy expenditure (Keys, Brozek, Henschel, Mickelson, & Taylor, 1950). However, it has been demonstrated that the Harris-Benedict equation of resting metabolic energy expenditure is unreliable in the malnourished patient (Roza & Shizgal, 1984). One potential source of this paradoxical finding may be hypermetabolic states facilitated by various cytokinergic-metabolic interactions that are unique to the cachetic state.
Body cell mass (BCM) can be anatomically subdivided into skeletal muscle and the visceral components (adipose tissue, extracellular matrix), with the skeletal portion occupying a much larger proportion of the BCM. BCM is disproportionally effected in states of disease related cachexia as the syndrome aggressively degrades the skeletal (lean) compartment to a greater degree than it does the visceral compartments, particularly the adipose tissue (although this does also occur as a result of increased lipolysis). In cases of (simple) starvation and subtypes of anorexia-induced weight loss, adipose tissue is the predominant source of stored fuel, not lean tissue, and after a period of relative adaptation, physiological mechanisms are activated which serve to protect the loss of lean tissue (i.e., ketosis). Because cachexia (particularly cancer associated cachexia) tends to develop at advanced states of neoplastic growth, preventing muscle waste in cancer patients is of critical importance (Argiles et al., 2003).
Evidence has accumulated that the lean tissue degradation in cachetic states is due to an increase in the degradation of skeletal muscle tissue rather than an inhibition of protein synthesis (Argiles et al., 2003). Further, it appears that both the proinflammatory cytokinergic response to the cancer state as well as tumor derived molecules themselves are responsible for this catabolic process. TNF-á is a pro-cachetic cytokine which has been shown to mimic the apoptotic response in muscle tissue of healthy animals (Carbo, Busquets, Van Royen, Avarez, Lopez-Soriano, and Argiles, 2002).
Proteolysis inducing factor (PIF), a tumor derived molecule, has also been shown to produce direct proteolys; not only in vivo but also in vitro (Lorite, Cariuk, and Tisdale, 1997). PIF appears to have a direct inhibitory effect on glucose consumption by skeletal muscle (a marker of anabolic activity). A protein member of the TGF-â family, myostatin, has been shown to be a strong negative regulator of muscle growth (Sharma, Langley, Bass, & Kambadur, 2001) and HIV-infected men with cachexia have shown increased serum levels of myostatin (Gonzalez-Cadavid et al., 1998), suggesting a possible role for myostatin in cachexia-type muscle atrophy (Jackman & Kandarian, 2004).
Skeletal muscle proteolysis may also be mediated by disruptions in the GhRh-GH-IGF-1 axis in both liver and muscle tissue. This disruption can occur either at the level of the ARC where GhRh cell bodies are located, or in muscle tissue itself, where IGF-1 is produced locally in response to GH. Again, proinflammatory cytokines have been suggested to be a putative underlying mechanism for these disruptions (e.g., TNF-á; IL-1â; Frost and Lang, 2005). An additional common pathway for skeletal muscle proteolysis may be mediated by disruptions in the HPG axis. GnRH perikarya in the supraoptic nucleus (SON) and preoptic area (POA) of the hypothalamus have evidenced volume reduction during prolonged negative energy imbalances. Reduced cell volumes and substrate flux through the HPG axis would result in decreases in the production of testosterone, a principal anabolic agent.
The cachetic increase in metabolic rate may be tied to systematic physiological processes in the skeletal muscle tissue. The uncoupling proteins (UCP) are a family of mitochondrial proteins that mediate proton leakage and decrease the coupling of respiration to ADP phosphorylation, resulting in the manufacturing of heat rather than ATP which is essential for anabolic activity (i.e., conversion, rather than loss of energy). Both UCP2 and UCP3 are expressed in human skeletal tissue and it has been demonstrated that their mRNA’s are elevated in skeletal muscle during tumor growth and that TNF-á is able to mimic the increase in gene expression of these proteins (Busquets, Sanchis, Alvarez, Ricquier, Lopez-Soriano, and Argiles, 1998).
The increase in anorexia noted in the cachetic state is most likely mediated by cytokine interaction with the homeostatic feedback control center of human energetics in the brain stem and hypothalamus. Typically, energy balance (i.e., food intake and energy expenditure) is controlled in these regions by specific neuronal populations which integrate peripheral blood-borne signals that convey information on energy and adiposity status (Laviano, Meguid, Inui, Muscaritoli, and Rossi-Fanelli, 2004). A key hypothalamic center for the recognition of these signals and the transduction of their information is the arcuate nucleus (ARC) and its associated bidirectional projections with the paraventricular (PVN) nucleus and lateral hypothalamic region (LH).
Evidence has recently begun to accumulate suggesting that the inability of the ARC-PVN and ARC-LH circuitry to appropriately respond to peripheral energy signals (particularly leptin) is mediated in large part by the same cytokines mentioned earlier which are released by the immune system in response to neoplastic tumor growth. Two significant cytokines contributing to this ‘hypothalamic resistance’ (Laviano et al, 2004) appear to be interleukin-1 (IL-1) and TNF-á. Thus, cytokine driven dysregulation of the hypothalamic monoamine system amplifies an already metabolically inefficient host system, contributing to a severe imbalance in the energetic equation. The situation then becomes what has been described as a condition in which “all the body can eat is itself” (Laviano et al., 2004).
Psychological Influences on the Cachetic-Anorexic Condition: a Role for Attachment
The majority of the research on cachexia has understandably focused on the mechanisms and pathways involved in its etiology and progression. In particular, because cachexia occurs in the presence of a disease or physiological insult (e.g., extensive burning) research has been predominately concerned with understanding the influence of various pro-inflammatory and tumor-derived cytokines. While the associated anorexic phenotype has been researched more globally with respect to etiology and neuroendocrine sequalae (i.e., anorexia-nervosa, obligate training [Chrousos, 1998], psychological contributions) little in the way of psychological contributions to the cachetic state have been directly examined. This is somewhat surprising given the large body of research in the psychoneuroimmunology and psychoneuroendocrinology literature which has evidenced the powerful role that psychological factors can have on disease/disorder etiology, progression, and outcome (for an excellent review, cf. Vedhara and Irwin, 2005).
The hypothalamic pituitary adrenocortical (HPA) axis and the sympathoandrenalmedullary (SAM) axis are two principle pathways through which psychological effects exert their profound impact on many disease states. At each step of the pathway, various neuropeptides, releasing factors, and hormones contribute to systemic effects on the extant disease state. Because many of the involved factors, peptides, and steroid hormones (e.g., cortisol) directly influence physiological process in both skeletal muscle tissue and central energetic homeostatic centers, the possibility that psychological factors can influence or amplify the cachetic state is highly likely.
A large body of evidence has accumulated indicating an epigenetic programming of stress response sensitivity in both non-human and human species and that individual differences in stress response activity is determined in large part through variations in maternal care (cf. Meaney et al., 1985; Liu et al., 1997; Francis et al., 1999; Fish et al, 2004; Schore, 1999). An additional natural outcome of variations in the early caregiving environment in humans is the establishment of discrete, quantifiable patterns of attachment (Bowlby, 1969/1973/1980; Ainsworth, 1978) relationships with their caregivers. These patterns of relating develop and evolve across the lifespan such that while the individual behaviors in the pattern may change, the pattern itself (of relating to both other and the self) tends to remain stable (although change is possible and is lawful).
In general, these patterns of relating to caregivers, later others, and finally cognitively reflecting back (in adulthood) on attachment experiences, can be considered secure or insecure. The secure individual evidences flexible and balanced emotional and behavioral regulation and is able to deal with stress adaptively. The insecure individual is not, and generally takes either the form of overresponsivness or overactivity to stressors or inhibiting /actively dampening adaptive regulatory emotional and behavioral responses to stress or challenge. In either case, challenge in the environment is met with an inefficient and ineffective behavioral or emotional (cognitive) strategy of effectively ‘metabolizing’ the stress. These insecure and secure patternings of both stress induced behavior and metacognitive processes, as well as environmental contexts associated with their emergence, have been consistently associated with altered biobehavioral processes (i.e., HPA organization and regulation; Spangler and Grossman, 1993; Gunnar et al., 2001; Cichetti and Rogosch, 2001; Gunnar and Donzella, 2002).
Life does not stop in the midst of a diagnosis of a life-threatening disease such as cancer or HIV and cachexia-anorexic conditions. In addition to the stressor of the being diagnosed with the disease itself, individuals will be confronted with daily life hassles and stressors. Thus, the ability to successfully cope or ‘metabolize’ more severe stressors becomes paramount for the individual. The insecure individual will show the worst ability to regulate in the face of increasing physical and emotional perturbation associated with the disease state. This failure to adaptively regulate emotion and/or overt behavior will lead to physiological disturbances in the bodies stress-regulatory and associated neuroendocrine and neuroimmune pathways, directly amplifying the progression of the cachetic-anorectic state.
At all levels of the HPA axis there appears to be grounds for an interactive matrix in which the various releasing factors and hormones serve to worsen the cachetic-anorectic state. For example, CRF has long been known to serve an important role in appetite regulation and energetics, blunting appetite while also serving to increase sympathoadrenalmedullary tone, leading to increased lipolysis and blood glucose levels (Schwartz, Dallman, and Woods, 1995). Chronic administration of CRF causes sustained anorexia and progressive weight loss and it appears that CRF blunts the adaptive hypothalamic response to weight loss through an inhibition of the NPY system (Inui, 1999; Heinrichs, Menzahgi and Koob, 1998).
Clearly, upregulation of CRF production due to environmental perturbation and a particular style of insecure emotional regulation by the patient could directly lead to increased anorectic sensations above that already produced by peripheral and local cytokine activation, thus widening the negative energy imbalance. Additionally, prolonged activation of the stress-system leads to suppression of GHRH production in the POA and ARC, and leads to an inhibition of somatomedin C and other growth factor effects on their target tissues, particularly skeletal muscle tissue (Chrousos and Gold, 1992). Thus, anabolic processes are severely constrained in the presence of both host and tumor affiliated factors that are propagating catabolic processes.
Both the secretion of glucocoritcoids (end products of the CRF-ACTH axis), and catecholamines (epinenephrine, norephinenephrine), are normal physiological responses to stress. However, prolonged activation of either one of these systems can have deleterious effects on muscle protein. Cortisol has long been known to facilitate degradation of body tissue (cf. Sapolsky, Krey, and McEwen, 1986 for an excellent review). In particular, prolonged cortisol release has been long known to both lead to muscle atrophy and immunosuppression.
The effects of the glucocorticoids on skeletal muscle tissue can either be direct (e.g., through modulation of myosin heavy chain isoform expression) or indirect through their effects on anabolic substrate flux into the skeletal muscle cells and protein synthesis therein. The synthetic glucocorticoid dexamethasone is widely used to induce muscle proteolysis either in vivo (Hasselgren, 1999) or in cell culture (Thompson et al., 1999). Both disuse atrophy and cachexia are associated with increases in circulating glucocorticoids, and so additional amplification via psychologically modulated increases in already heightened glucocorticoid levels would serve to hasten the muscle tissue wasting associated with the cachetic state. At this point it should be recalled that glucocorticoids themselves will exert their own effects on tumor growth, both establishing their promotion and accelerating their growth (Sapolsky et al., 1986).
In addition to glucocorticoids, the catecholamines are also regulated in part by psychological stress and they too have catabolic effects on lean tissue outside of their well known impact on adipose reserves. For example, Herndon, Hart, and Wolf (2001) showed that the administration of the â-adrenergic antagonist propranalol to children burned over more than 40% of their total body surface area improved muscle protein balance. Ertbjerg, Lawson, and Purslow (2000) found that epinenephrine treatment for 18h decreased total protein content of C2C12 cells in vitro. One line of evidence suggests that the negative effects of prolonged peripheral sympathetic effects on skeletal muscle may be mediated by the activation of proinflammatory cytokines within skeletal muscle tissue, most notably IL-6 (Frost and Lang, 2005).
In sum, the available evidence suggests that maladaptive reactivity to psychological stressors, via modulations in the HPA and SAM pathways, can exacerbate extant cachetic-anorectic conditions. This can lead to increased muscle wasting and immunosuppression either directly via actions on muscle tissue, or indirectly by acting on the homeostatic energetic system to decrease energy intake. However, it is important to note that different stressors may affect individuals differently and therefore have divergent effects on the cachetic-anorexic state. As noted in a unpublished contribution by this author (Haltigan, 2005), Herman and Cullinan (1997) identified two divergent stress pathways known as the systemic and processive stress pathways.
While the systemic stress pathway is acute and is activated in life-threatening situations such as hypoxia and involves the locus ceruleus-norepinephrine (LC-NE) system (with direct projections to the PVN), the processive stress pathway is not life-sustaining and requires input from multiple sensory modalities prior to the initiation of a stress-response. This pathway is “limbic sensitive” (Herman and Cullinan, 1997) and may reach the PVN through projections such as the stria terminalis and the ventral amygdalofugal pathway, both of which originate in (or course through) emotional centers of the brain (e.g. amygdala, hippocampus), where affect regulatory content is stored.
The processive pathway can be conceptualized as the primary pathway through which psychological processes influence the cachetic-anorectic state. Processive stressors by nature require emotional integration and the application of insecure or secure regulatory strategies. Attachment theory suggests that through interactive (caregiver) assistance in the struggle to organize thoughts, feelings, and behaviors in personally satisfying and socially constructive ways, the developing individual becomes able to adaptively cope with threats to their own health and safety or their loved ones (Steele and Steele, 2005). As an adult, this is reflected in a coherent and balanced description of attachment related experiences in their own childhood as revealed in the Adult Attachment Interview (AAI; George, Kaplan, & Main, 1985; Main & Goldwyn, 1985/1994). These individuals show an ability to acknowledge distress in past attachment experiences (if they occurred) and show a range of strategies (both intrapersonal and interpersonal), for managing and resolving negative emotions.
In contrast, insecure individuals may give a false positive picture of their attachment history (i.e., idealization), one that is highly derogating or dismissive with regard to attachment experiences, or one that lacks emotional engagement. Additionally, insecure individuals may also demonstrate a restricted and burdensome strategy of dealing with negative emotion, which is marked either by angry-escalation or of quiet, passive despair. Given their maladaptive styles of emotional regulation and coping—in response to processive stressors (e.g., the death of a loved one), these individuals may be at greater risk for prolonged, dysfunctional activation and pathogenic stasis of the neuroendoimmune pathways outlined earlier.
Chronic activation of these pathways due to maladaptive regulation in the face of processive stressors would lead to amplification of an extant cachetic-anorexic state that further creates energetic imbalances and promotes skeletal muscle tissue degradation as well as further immunosuppression.
Effective treatment and intervention with the cachetic-anorectic patients and similar subgroups with metabolic-energetic abnormalities would benefit from a greater understanding of the role played by psychological factors (particularly attachment), in facilitating disease progression. It may well be that through effective intervention (e.g., counseling) additional allostatic drive on cachetic symptomatology can be reduced and or even ameliorated. In addition, factors such as nutritional and resistance-training paradigms can be fully integrated into multifaceted treatment modalities targeted at attenuating or slowing the cachetic-anorectic state.
Currently, while nutritional regimes seem to be emphasized, both relationally anchored clinical therapy and strategic resistance-training protocols need to be considered. Collectively, all three would jointly attack the different source points in a bidirectional system. That is, neuroendoimmune mechanisms, emotional regulatory abilities, and direct skeletal muscle tissue processes would be targeted.
Current nutritional support for cachetic-anorectic patients has focused on increased food intake with given macronutrient profiles so as to avoid premature satiety (Laviano et al., 2005). Nutritional supplementation with Omega-3 fatty acids has shown some promise, most likely due to the role of both eicosapentaenoic acid (EPA) and docosahexaenoic (DHA) to suppress production of proinflammatory-procachetic cytokines and arachidonic acid-derived mediators. In addition, drug therapy in conjunction with nutritional support has shown some additive effect. Drug therapy has typically consisted of anticytokine agents, such as IL-6 monoclonal antibodies, as well as anti-serotonergic agents, ghrelin-infusion and anti-inflammatory agents such as cycloxygenase inhibitors (Cahlin et al., 2000).
Because of the severely impaired muscle strength and associated global fatigue with the cachetic-anorectic state, resistance training has not been considered in spite of increasing research demonstrating the cellular processes by which contractile activity stimulates hypertrophy. It has been long known that contractile activity and acute or progressive overload in skeletal muscle stimulates protein synthesis, leading to increased fiber size and strength, as well as modifications in metabolic properties (Booth et al., 1998; Williams et al., 1987). Current research is expanding on these findings by elucidating the intracellular pathways responsible for this hypertrophy which appear to include activation of the phosphatidylinositol 3-kinase signaling substrate mammalian target of rapamycin (mTOR; Parkington et al., 2003), a regulator of muscle cell growth and myogenesis. It may be that graded resistance training with these patients (in a group or clinical-trainer approach) along with collateral nutritional considerations, may prove to be fruitful in at least halting the process of skeletal muscle degradation.
Clinical treatment for the cancer-cachetic patient, as well as patients afflicted with other similar diseases may benefit from attachment-based theoretical approaches to clinical therapy (cf. West and Sheldon-Keller, 1994) as well as a blend of cognitive-behavioral techniques designed to promote the development of coping strategies to attenuate the physiological sequalae of psychological stress and maladaptive emotional regulation. These techniques might include guided relaxation training, anger management, and cognitive restructuring. A related approach might include components of dialectical behavior therapy (DBT; Linehan,1993).
Effective treatment and intervention with the cachetic-anorexic patient depends on an understanding of the diverse physiological and neurochemical abnormalities presented by the cachetic-anorexic state. It also depends on the effect that individual differences in emotional regulation will have on the progression and severity of the condition. With regard to the psychological component, most research has examined the role that various DSM defined mental disorders have on disease processes. However, the syndrome descriptions in the DSM are without implication for treatment. On the other hand, if assessment of patient psychological status was based in attachment theory (e.g., the AAI for adults) then a greater understanding and framework for intervention is achieved. Indeed, it has been argued (Widiger and Frances, 1985) that personality disorders can be more aptly characterized by difficulties in interpersonal relationships and that this ‘interpersonal dimension’ is of particular relevance to DSM defined Axis II personality disorders. In essence, a personality disorder may be a disorder of interpersonal relatedness. (Widiger and Frances, 1985).
Summary and Future Directions
Presented here is a psychoneuroendoimmune model of how psychological factors—viewed from an attachment perspective—can contribute to the worsening of a disease state that dramatically compromises quality of life for the stricken patient, and in some cases can be the primary factor in the disease-related death. Attachment is conceptualized as augmenting the cachetic-anorexic state through various ‘insecure’ emotional regulatory strategies which lead to maladaptive stress-generated activity of the HPA and SAM neuroendocrine systems.
Neurochemical and hormonal products at all levels of this intricate system serve to reinforce and buttress the basal level of cachetic-anorexic activity generated by the disease itself. Because the disease state itself is a source of major life stress (and because it may activate memories of past life events and future projections in what may become of interpersonal relations), attachment is well suited to understand many of the psychological contributions to and interactions with the cachetic-anorexic state.
Future research should seek to evaluate intervention programs premised on the philosophy espoused here. Comparison of disease stricken individuals identified as ‘insecure’ before and after intervention should be undertaken. Markers of disease progression and advancement, including levels of pro-cachetic cytokines, skeletal muscle proteolysis, catabolic hormones, and anorexigenic peptides can be quantified to determine if reductions have occurred. Consideration of additional variables, such as drug treatment and other medical treatments can be controlled for through the use of structural equation models which allow the identification of unique contributions to improvements in the cachetic-anorectic state. Most importantly, self-report measures of the patients feeling state and perceived quality of life can be assessed both prior to and after treatment.
As pointed out by others (e.g., Damasio, 1994) separating the brain or mind from the body may not be a profitable approach when considering and understanding medical and emotional disorders. By integrating information from disciplines across psychology, endocrinology, immunology, oncology, neuroscience, and general medicine, it may be possible to better understand and treat both terminal diseases themselves as well as the associated atypical disease states they spawn.
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