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Pathophysiology

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Introduction

The pathophysiology of Cancer Anorexia Cachexia is driven by a variable combination of reduced food intake and abnormal metabolism that leads to a negative protein and energy balance (Figure 1).1,2

There has been great progress in understanding the underlying mechanisms of cachexia and recent literature reports that many of the primary events driving Cancer Anorexia Cachexia are likely mediated via the central nervous system.2,3

Also hypercatabolism and hypoanabolism associated with cachexia seem to be provoked by an increase in systemic inflammation and catabolic factors and a decrease in anabolic mediators that can act partially via the central nervous system and that affect via direct and indirect mechanisms peripheral target organs including adipose tissue and striated muscle. 2,4

Recent literature reports that many of the primary events driving cachexia are likely mediated via the central nervous system.2

In this context, it is important to consider that body weight and metabolism are controlled by the brain and energy homeostasis is established in the body through a system of highly regulated controls. Particularly, specific hypothalamic nuclei integrate cognitive, visual and sensory inputs; and peripheral signals indicate body energy reserves, the activity of the gastrointestinal tract and nutrient intake. Thanks to these controls the organism can store energy optimally or, conversely, mobilize reserves under appropriate circumstances.2  

Additionally, patients with cancer are characterized by a reduced food intake due to primary anorexia which can be increased by secondary nutritional impact symptoms (Figure 2).2

Nutrition impact symptoms Number (%)
Early satiety 94 (62%)
Constipation 78 (52%)
Nausea or vomiting 67 (44%)
Depressed mood 63 (42%)
Dysgeusia 42 (28%)
Dysphagia 21 (14%)
Dry mouth 14 (9%)
Mucositis 11 (7%)
Dental pain 8 (5%)

Prevalence of secondary nutritional impact symptoms (S-NIS) in patients referred to a cachexia clinic5

Relevant to patient’s nutritional intake is the negative impact of antineoplastic therapies. Particularly, chemotherapy and radiotherapy cause swallowing difficulties and other side effects such as anorexia, nausea, vomiting, mucositis, taste change, or lethargy. Furthermore, surgical patients may be fasted for prolonged periods perioperatively, further deteriorating the nutritional state of these patients.3

Pathophysiologic mechanisms contributing to Cancer Anorexia Cachexia

Cancer Anorexia Cachexia is described as a multifactorial syndrome in which systemic inflammation, reduced food intake and altered metabolism contribute to loss of muscle mass and reduction in body weight. The mechanisms of Cancer Anorexia Cachexia are complex and still not entirely clarified. Nevertheless, common themes emerge in terms of cytokine/neuroendocrine-driven changes in food intake, altered hepatic and skeletal muscle protein synthesis/degradation, and adipocyte lipolysis.4

A schematic representation of integrative physiology of Cancer Anorexia Cachexia is given in Figure 3, and the main mechanisms are presented in the following sections.

Inflammation

One proposed mechanism of Cancer Anorexia Cachexia consists of an integrated physiological response of substrate mobilization driven by inflammation. In this context, inflammation is seen as a unifying mechanism for the entire cluster of sickness behaviors including not only anorexia but also fatigue, sleep disturbances, mood alteration, lethargy, depression, fever, anhedonia, cogni­tive impairment, hyperalgesia and decreased social inter­action. Recent studies also suggest that inflammation plays a role in the increased lipolysis in adipose tissue and increased muscle proteolysis.

The tumor and a diversity of host cells (e.g. skeletal muscle, adipose tissue and cells of the immune system and liver) induce an inflammation response, which acts on the brain and target organs in the periphery. High levels of TNF-α, IL-6, and IL-1 have been found in some patients with cancer. It is still unclear whether the cytokine production is primarily from the tumor or the host immune response, but it has been hypothesized that these mediators could be the source of the acute phase protein response (APPR) seen in many malignancies and in Cancer Anorexia Cachexia.6,7

At present, several cytokines have been hypothesized to play a role in the etiology of Cancer Anorexia Cachexia, including tumor necrosis factor-α (TNF-α), interleukin -1 (IL-1), interleukin-6 (IL-6), and interferon-γ (IFN-γ). 3,4

The identity of specific inflammation mediators involved in Cancer Anorexia Cachexia are still being studied.2

Catabolism

In cancer patients a number of factors increase the catabolic response. These factors include tumor progression, comorbid conditions, old age, physical deconditioning, nutritional deficiency, drugs (i.e. chemotherapy) and other medical interventions (i.e. surgery, radiotherapy). This increased catabolic response leads to unsustainable levels of fat and muscle mobilization and levels of muscle depletion that cause significant morbidity and mortality.2

Cancer Anorexia Cachexia is also associated with downregulation of most anabolic pathways including a decrease in IGF-1 levels and testosterone that are likely to worsen the decrease in muscle mass and strength, and the increased fatigue seen in this setting. As a possible compensatory response to weight loss, ghrelin levels have been observed to increase in patients with Cancer Anorexia Cachexia. 8,9

The tumor has a significant role in determining the catabolism response: it alters energy regulation by eliciting an excessive inflammatory response, which will augment both central and peripherally mediated catabolic events. Also, the tumor directly consumes macronutrients, especially in late-stage disease, when the overall tumor mass reaches >0.75 kg and the energy consumption of the tumor is quantitatively important.9

Moreover, patients with cancer are prone to physical deconditioning and to nutritional deficits due to their overall health status. Inactivity (due to bed rest, peripheral neuropathy, etc.) causes muscle wasting, potentiates catabolic signals and desensitizes muscle to anabolic signals.2

Dysregulation of the neuropeptidergic circuitry controlling food intake and energy expenditure

Food intake is a complex, multifaceted process that is regulated by a combination of centrally derived hormonal signals, together with hormonal and neural signals originating in the periphery.

Several neuropeptides have been identified over the past few decades, which act in the brain to alter food intake and energy expenditure.10

A key player in the physiologic regulation of appetite/food intake, as well as in conditions of anorexia - cachexia, is the hypothalamus, where the integration of peripheral signals occurs. Some of these signals inhibit energy intake (such as adipocyte-derived leptin), while other signals stimulate energy intake (such as stomach-derived ghrelin). The arcuate nucleus (ARC) in the hypothalamus integrates these inputs to modulate food intake via second-order neurons. According to the information conveyed to the brain, peripheral signals may differentially activate or inhibit orexigenic and anorexigenic signals. When an energy deficit is signaled, for example in starvation, orexigenic neurons are activated and anorexigenic neurons are inhibited, resulting in increased energy intake. Conversely, when an energy excess is signaled, orexigenic neurons are inhibited and anorexigenic neurons are activated3 (Figure 4a).

In cancer patients, cytokines can elicit effects that mimic leptin signaling and suppress orexigenic ghrelin and neuropeptide Y (NPY) signaling, inducing sustained anorexia and cachexia unaccompanied by the usual compensatory response. Increased brain cytokine expression disrupts hypothalamic neurochemistry, particularly in the ARC where cytokines activate anorexigenic neurons, while inactivating orexigenic neurons. The anorexia and weight loss associated with cachexia may occur through persistent inhibition of the NPY orexigenic network and through stimulation of the anorexigenic neuropeptides.1,3 (Figure 4b). This also takes place in spite of an appropriate response from peripheral signals (i.e. an increase in ghrelin and a decrease in leptin levels).

Different studies have proven that total ghrelin levels are elevated-approximately 25% above normal-in a variety of cancers causing cachexia: lung, breast, colon, and prostate cancers. Moreover, high levels of acyl ghrelin have been measured in patients with Cancer Anorexia Cachexia. Interestingly, ghrelin elevation in many of these Cancer Anorexia Cachectic patients was still associated with poor appetite and weight loss. This has led some to postulate a possible state of ghrelin resistance, or a net anorectic effect of other processes in Cancer Anorexia Cachexia, that cannot be overcome even by reactive increases in endogenous ghrelin production. More recently, it has been suggested that administration of supraphysiologic doses of exogenous ghrelin or ghrelin receptor agonists may have a beneficial effect in this setting in spite of the already elevated circulating ghrelin levels. This would be analogous to the effects of administering insulin in individuals with type 2 diabetes where its effects are still present even in the presence of hyperinsulinemia and insulin resistance.11

Alteration of skeletal muscle protein synthesis/degradation

Mechanisms regulating skeletal muscle mass.

In adults, protein synthesis and degradation generally remain in balance and thus muscle mass remains fairly constant in the absence of stimuli (e.g. exercise). Anabolic pathways leading to protein synthesis in muscle are mediated by the activation of the serine/threonine kinase Akt, resulting in downstream amplification of the mTOR (mammalian target of rapamycin) that leads to increased muscle protein synthesis. The muscle anabolic pathway is upregulated by a variety of stimuli, including insulin-like growth factor-1 (IGF-1), branched chain amino acids (e.g. leucine), exercise and testosterone.


Protein breakdown in the skeletal muscle is instead driven by the activation of the ubiquitin proteasome pathway and caspases; this process is under the transcriptional control of the transcription factors Fox-O (forkhead O) and NF (nuclear factor)-κB.12 In catabolic states where proteolysis is increased, two genes specific to muscle atrophy, MuRf1 (Muscle Ring-finger protein-1) and MAFbx (muscle-atrophy F-box protein, also called Atrogin-1), are upregulated: these encode ubiquitin ligases, which bind to and mediate ubiquitination of myofibrillar proteins for subsequent degradation during muscle atrophy.13

The most evident metabolic explanation for skeletal muscle decline in Cancer Anorexia Cachexia is an imbalance between protein catabolism and anabolism; in addition to an increase in catabolism, a reduction in anabolism has been shown to occur.3  

Muscle atrophy in Cancer Anorexia Cachexia

In Cancer Anorexia Cachexia, muscle atrophy occurs, which results from a depression in protein synthesis, and an increase in protein degradation or from a combination of both. Skeletal muscle loss in Cancer Anorexia Cachexia can be mediated by multiple factors derived from tumor and host cells. Recently, it has become evident that specific molecules are upregulated (e.g. myostatin) whereas other factors (e.g, insulin-like growth factor 1 [IGF-1]) are downregulated in Cancer Anorexia Cachexia (Figure 5).3

Myostatin upregulation

has been observed in the pathogenesis of muscle wasting during Cancer Anorexia Cachexia.6Myostatin is a cytokine that is mostly expressed in skeletal muscles and is known to play a crucial role in the negative regulation of muscle mass. Upon binding to the activin type IIB receptor, myostatin can initiate several different signaling cascades, resulting in decreased muscle growth and differentiation. Muscle size is regulated via a complex interplay of myostatin, cytokines and other markers signaling through IGF-1/PI3K/Akt pathway, which is responsible for increased protein synthesis and decrease protein degradation in muscle (Figure 6). This protein degradation involves activation of several pathways including the ubiquitin-proteasome pathway, autophagy and apoptosis. Therefore, the regulation of muscle weight is a process in which myostatin plays an important role, although its mechanism of action and the role of the signaling cascades involved are not fully understood.


One of the main positive regulators of muscle growth is IGF-1. Under normal condition, IGF-1 signaling seems to be dominant and block the myostatin pathway. However, an inhibition of IGF-1 was observed when myostatin was overexpressed.6 Also other cytokines (especially TNF-α, IL-1, IL-6, and IFN-γ) have been implicated in the induction of cancer-related muscle loss.3

Adipocyte lipolysis

In Cancer Anorexia Cachexia, loss of adipose tissue results partly from reduced food intake, as well as from tumor factors and systemic inflammatory cytokines that function by either inhibiting lipogenesis or by promoting lipolysis.4 Results from clinical studies suggest that adipose depletion in cachexia occurs by lipolysis. In this model, fat atrophy results from the mobilization of lipids that constitute 95% of fat cell volume.4 Specifically, triglycerides are hydrolyzed to free fatty acids (FFAs) and glycerol, which are then released in the circulation. The rate-limiting enzymes catalyzing this reaction are the hormone sensitive lipase (HSL) and adipose triglyceride lipase (ATGL). Both HSL activity and plasma FFA and glycerol increase considerably in Cancer Anorexia Cachectic patients (Figure 7).4

Conclusions

The mechanisms of Cancer Anorexia Cachexia are complex and multifactorial. Although the etiopathogenesis of Cancer Anorexia Cachexia is not entirely understood, multiple biologic pathways are known to be involved: procachectic signals from tumor cells, systemic inflammation in the host, and metabolic changes. Cytokines seem to play a major role in Cancer Anorexia Cachexia, but other mediators are involved in the pathophysiology of Cancer Anorexia Cachexia and studies are ongoing to shed light on this scenario. A better understanding of the molecular mechanisms of Cancer Anorexia Cachexia may identify novel targets for new approaches to this impactful condition.

References

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