Cancer cachexia syndrome in head and neck cancer patients Part II Pathophysiology by bettysampson

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									BASIC SCIENCE REVIEW
Robert L. Ferris, MD, PhD, Section Editor




CANCER CACHEXIA SYNDROME IN HEAD AND NECK CANCER
PATIENTS: PART II. PATHOPHYSIOLOGY
Jonathan George, BA,1 Trinitia Cannon, MD,2 Victor Lai, MD,1 Luther Richey, BA,1
Adam Zanation, MD,2 D. Neil Hayes, MD,3,4 Carol Shores, MD, PhD,2,4 Denis Guttridge, PhD,5
Marion Couch, MD, PhD2,4
1
  Doris Duke Clinical Research Fellowship, The Verne S. Caviness General Clinical Research Center,
University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7070
2
  Department of Otolaryngology/Head and Neck Surgery, University of North Carolina School of Medicine,
G0412 Neurosciences Hospital, Chapel Hill, North Carolina 27599-7070.
E-mail:
3
  Division of Medical Oncology, Department of Internal Medicine, University of North Carolina School of
Medicine, Chapel Hill, North Carolina 27599
4
  Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill,
North Carolina, NC 27599
5
  Division of Human Genetics, Department of Molecular Virology, Immunology and Medical Genetics,
The Arthur G. James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210

Accepted 22 December 2006
Published online 27 March 2007 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hed.20630




                                                                          and inflammatory cytokines, and neuroendocrine dysfunction.
Abstract:     Cancer cachexia is a morbid wasting syndrome
                                                                          These culminate to create an energy-inefficient state character-
common among patients with head and neck cancer. While its
                                                                          ized by wasting, chronic inflammation, neuroendocrine dysfunc-
clinical manifestations have been well characterized, its patho-
                                                                          tion, and anorexia. V 2007 Wiley Periodicals, Inc. Head Neck
                                                                                                C
physiology remains complex. A comprehensive literature search
                                                                          29: 497–507, 2007
on cancer cachexia was performed using the National Library of
Medicine’s PubMed. The Cochrane Library and Google search                 Keywords: cancer cachexia and anorexia; muscle wasting;
engine were also used. Recent evidence and new concepts on                weight loss
the pathophysiology of cancer cachexia are summarized. Tar-
geted therapies are presented, and new concepts are high-
lighted. Cancer cachexia is characterized by complex, multilevel
pathogenesis. It involves up-regulated tissue catabolism and
impaired anabolism, release of tumor-derived catabolic factors            INTRODUCTION
                                                                          Despite recent advances in treatment, clinical
Correspondence to: M. Couch
                                                                          dilemmas persist for the surgeon treating patients
                                                                          with head and neck cancer with marked weight
Contract grant sponsor: University of North Carolina’s General Clinical
Research Center (GCRC); contract grant number: RR00046; Contract          loss. At initial presentation, it is often difficult to
grant sponsor: Doris Duke Clinical Research Program.                      accurately determine the cause of lost weight. The
V
C   2007 Wiley Periodicals, Inc.                                          patient may be experiencing weight loss because


Cancer Cachexia Pathophysiology                                                 HEAD & NECK—DOI 10.1002/hed           May 2007       497
of cancer-induced odynophagia, aging, immobility,       and proteolysis-inducing factor (PIF). The UPS is
anorexia, chemoradiation therapy, cancer ca-            an important pathway for muscle protein degra-
chexia, starvation due to mechanical obstruction,       dation that appears to be up-regulated in animal
or malnutrition due to alcoholism. Of these, can-       models of cancer cachexia. The DGC is a cytoarch-
cer cachexia is the least understood cause of           itectural framework in muscle cells whose dys-
weight loss, and yet it is responsible for the great-   function may help initiate muscle wasting.
est morbidity among patients with head and neck         Finally, PIF is a tumor-derived catabolic factor
cancer.                                                 that may initiate and augment muscle wasting in
    The clinical manifestations of this syndrome        humans.
have been characterized previously.1 They include           Current research on the pathogenesis of can-
skeletal muscle and adipose tissue wasting, exag-       cer cachexia posits that exuberant release of
gerated systemic inflammation, and anorexia.             proinflammatory cytokines, such as interleukin
Recent findings have shed light on the pathologic        (IL-) 1b, IL-6, tumor necrosis factor alpha (TNF-
basis for these manifestations. Skeletal muscle         a), and interferon gamma (IFN-g), causes skeletal
and adipose tissue wasting appear to be mediated        muscle proteolysis through suppression of muscle
by dysfunction in several overlapping pathways.         genes and activation of ubiquitin–proteasome-
First, dysregulation of muscle-specific cellular         mediated proteolysis.4–6 These circulating proin-
components such as the ubiquitin–proteasome             flammatory cytokines inhibit the expression of
system (UPS) and the dystrophin glycoprotein            myosin heavy chain genes, leading to dissociation
complex (DGC) facilitates muscle catabolism.2,3         of myosin from its contractile apparatus in muscle
Tumor-derived catabolic factors and circulating         cells. Free myosin is degraded by the UPS, whose
proinflammatory cytokines also augment muscle            components are activated by these same cyto-
and adipose tissue catabolism. Finally, disruption      kines. Ubiquitin–proteasome-mediated muscle
of neuroendocrine pathways leads to anorexia.4          protein catabolism is also inducible by PIF, a pur-
The aim of this review is to clarify the mecha-         ported tumor-derived catabolic factor.7 Current
nisms involved in the pathogenesis of cancer            research also suggests that muscle breakdown in
cachexia and to describe potential targets for anti-    cachexia involves cellular dysregulation of the
cachexia treatment.                                     DGC, a membrane structure responsible for main-
                                                        taining the functional integrity of muscle cells.3
                                                        Here we will describe 3 important components of
SKELETAL MUSCLE                                         skeletal muscle proteolysis in cancer cachexia: the
The most prominent clinical feature in cancer           UPS, PIF, and the DGC.
cachexia is progressive loss of skeletal muscle
mass. This may approach 75% reduction in skele-         Up-regulation of the Ubiquitin–Proteasome System.
tal muscle protein mass, even with a total weight       The UPS is a 750-kDa tube-like structure found
loss of only 30%.1 Loss of muscle protein plays a       within cells. This structure is hypothesized to be
major role in the shortened survival time of ca-        an important pathway underlying catabolic dis-
chectic cancer patients, who experience a final          ease states such as starvation, sepsis, denervation
common pathway of progressive physical disabil-         atrophy, severe trauma, and cancer cachexia.8
ity and impairment of respiratory function. Cur-        It is the major catabolic pathway in cancer
rent data suggest that loss of muscle protein is        cachexia,9 and its overactivation has been repro-
mediated primarily by accelerated protein catabo-       duced by nearly all rodent models of cancer-associ-
lism, but that impaired protein anabolism is also       ated muscle wasting tested thus far.10 Further-
important. These appear to be 2 dynamic and             more, research on human subjects with cancer
interrelated processes that ultimately account for      has also demonstrated UPS overactivation.11
the progressive muscle wasting seen in cancer              Most intracellular proteins in skeletal muscle
cachexia.                                               are degraded through the UPS proteolytic system.
                                                        Muscle protein degradation involves enzymatic
                                                        marking of proteins with multiple ubiquitin mole-
ACCELERATED MUSCLE CATABOLISM                           cules in a multistep process that culminates in
Three important and recently identified factors          protein degradation within the proteasome. In the
play central roles in skeletal muscle wasting in        first step of this marking process, multiple ubiqui-
patients with cancer cachexia. These are the ubiq-      tin molecules are covalently conjugated to con-
uitin–proteasome proteolytic system, the DGC,           tractile proteins by ubiquitin-activating (E1),


498   Cancer Cachexia Pathophysiology                              HEAD & NECK—DOI 10.1002/hed   May 2007
                                                                 suppresses the induction of MAFbx and MuRF1,
                                                                 preventing muscle wasting.15 This indicates a
                                                                 potential avenue for future therapy of cachexia.
                                                                     Accelerated muscle catabolism in cancer cach-
                                                                 exia thus appears to result from cytokine-medi-
                                                                 ated induction of the muscle-specific ubiquitin
                                                                 ligase genes MuRF1 and MAFbx and consequent
                                                                 activation of UPS proteolysis (Figure 3). The
                                                                 developing understanding of this system creates
                                                                 new targets for the treatment of cachexia. Gene
                                                                 knockout, MuRF1 and MAFbx suppression by
                                                                 IGF-1, and direct proteasomal inhibition might
FIGURE 1. The ubiquitin–proteasome system. Proteins like
                                                                 become targets for anticachexia treatment in the
myosin are marked for degradation in the proteasome by con-
jugation with polyubiquitin chains. Proteolytic enzymes in the   future.
proteasome complex then degrade these ubiquitinated (Ub-)
proteins into peptides. Ub, ubiquitin.                           Induction of Muscle Breakdown by Proteolysis-
                                                                 Inducing Factor.   PIF is a 24-kDa glycoprotein
ubiquitin-conjugating (E2), and ubiquitin-ligating               produced by tumor cells in both mice and humans
(E3) enzymes. In the second step, tagged proteins                that has been hypothesized to be responsible for
are recognized and degraded within the 26S pro-                  cancer cachexia.16 PIF has been found in many
teasome complex, whose catalytic core is lined                   human tumor types, including breast, ovarian,
with proteolytic enzymes. The proteasome then                    pancreatic, and colorectal tumors,1 and has been
releases oligopeptides that are rapidly degraded                 isolated from the urine of patients with cachectic
into amino acids by cytosolic peptidases. These                  cancer with weight loss.17 Furthermore, PIF
amino acids are then transported to the liver,                   appears to be present in patients with tumor-
where they are converted to acute-phase proteins                 related cachexia, but absent in cancer patients not
in an energy-wasting cycle that exacerbates                      losing weight, or in weight-losing patients with
inflammation and disrupts physiologic protein                     benign disease.18 Longitudinal studies have
balance (Figure 1).                                              shown that cancer patients expressing PIF in
    Proinflammatory cytokines such as IL-6, TNF-
a, and IFN-g have been shown to up-regulate
muscle-specific expression of important compo-
nents of the UPS.8 Recent data suggest that cyto-
kine-mediated induction of 2 muscle-specific ubiq-
uitin ligase genes, muscle ring-finger 1 (MuRF1)
and muscle atrophy F box (MAFbx), may be major
steps the induction of in skeletal muscle atrophy
in cachexia.12 Importantly, TNF-a- and IL-6
induce muscle-specific expression of IKK (in-
hibitor of NF-jB). This activates nuclear factor
kappa B (NF-jB) and causes MuRF1 up-regula-
tion, which results in severe muscle wasting in
mice.13 Thus, the IKK/NF-jB/MuRF1 pathway is
a cytokine-inducible signaling pathway that
appears to mediate skeletal muscle wasting in
cancer cachexia14 (Figure 2).
    There appears to be a similar pathway for
induction of the ubiquitin ligase gene MAFbx and
subsequent activation of UPS proteolysis. In cul-                FIGURE 2. Induction of the ubiquitin ligase MuRF1 and muscle
tured myotubes undergoing atrophy, MAFbx                         wasting in mice. Graph and Western blot showing the relation-
                                                                 ship of MuRF1 induction with decrease in fiber diameter in mice
induction is associated with inhibition of the
                                                                 with colon-26 adenocarcinoma. Glyceraldehyde-3-phosphate de-
PI3K/Akt pathway, a pathway normally associ-                     hydrogenase is a housekeeping gene used as a control. MuRF1,
ated with muscle hypertrophy. Activation of this                 muscle ring-finger 1, a gene for the ubiquitin ligase enzyme;
pathway with insulin-like growth factor 1 (IGF-1)                GADPH, glyceraldehydes-3-phosphate dehydrogenase.



Cancer Cachexia Pathophysiology                                        HEAD & NECK—DOI 10.1002/hed           May 2007      499
                                                                     cer-induced muscle wasting.3 Muscles from colon-
                                                                     26 adenocarcinoma-bearing mice exhibited mem-
                                                                     brane abnormalities associated with reduced lev-
                                                                     els of dystrophin and increased glycosylation of
                                                                     proteins within the DGC. The dysregulation of the
                                                                     DGC correlates positively with weight loss in
                                                                     patients with gastroesophageal adenocarcinoma.3
                                                                     Also, mutant mice lacking the protein dystrophin
                                                                     show enhanced tumor-induced wasting, while
                                                                     transgenic animals expressing dystrophin—spe-
                                                                     cifically in skeletal muscle—are spared from dis-
                                                                     ease.3 These findings suggest that the loss of func-
                                                                     tion of the DGC may cause muscle wasting in can-
                                                                     cer cachexia.
                                                                         Whether dysfunction of the DGC initiates,
                                                                     maintains, or promotes muscle breakdown in can-
FIGURE 3. TNF-a-mediated activation of ubiquitinating                cer cachexia is currently unclear. Overexpression
enzymes. TNF-a up-regulates the expression of the ubiquitin
ligase enzyme MuRF1 in an NF-jB–dependent manner. This
                                                                     of dystrophin appears to block the induction of
may be 1 mechanism by which proinflammatory cytokines                 MuRF1 and MAFbx but does not affect NF-jB
mediate muscle wasting in cachexia. This process appears to          activation in these muscles.3 This suggests that
involve several signaling factors that are part of the NF-jB path-   dysfunction within the DGC may mediate UPS-
way, including the Ikk complex (with subunits a, b, and g), p65,     dependent muscle breakdown in a manner inde-
and p50. TNF-a, tumor necrosis factor alpha; NF-jB, nuclear
factor kappa B; MuRF1, muscle ring-finger 1; TNFR, tumor ne-
                                                                     pendent of NF-jB. However, the exact mechanism
crosis factor receptor; IjB, inhibitor of nuclear factor kappa B;    of this dysfunction remains to be elucidated
Ijj, inhibitor of nuclear factor kappa B kinase.                     (Figure 4).


their urine lose weight over time, while patients
not expressing this factor gain weight.17 PIF                        IMPAIRED MUSCLE ANABOLISM
administration to mice and to cultured myocytes                      Although accelerated skeletal muscle wasting ap-
rapidly induces muscle catabolism, while PIF-                        pears to be a primary mediator of cancer cachexia,
induced weight loss in mice is reversed with anti-                   another important feature is impaired skeletal
PIF monoclonal antibodies.18                                         muscle anabolism. One study found that the total
    PIF induces muscle wasting by several mecha-                     body protein synthesis in healthy individuals was
nisms. First, it induces the muscle-specific release                  53%, whereas in cachectic individuals it was only
of 15-hydroxyeicosatetraenoic acid, activating                       8%.19 Several pathways appear to be involved in
UPS-mediated proteolysis.18 PIF also stimulates                      reduced skeletal muscle anabolism in cachexia.
the activation of NF-jB in tissue culture, which                     These include imbalance in the physiologic amino
facilitates the release of proinflammatory cyto-                      acid pool, reduced myosin expression, and up-reg-
kines and induces UPS-mediated proteolysis.8                         ulation of the gene regulator myostatin.
Thus, by stimulating the release of proinflamma-
tory cytokines and activating the UPS, PIF
expression generates a series of events culminat-
ing in skeletal muscle wasting.

Dysregulation of         the     Dystrophin      Glycoprotein
Complex.    New   research shows that cancer
cachexia may also involve the loss of an essential
muscle protein complex. The DGC is a muscle-spe-
cific protein manifold that anchors sarcomere
membranes in place and prevents them from being
                                                                     FIGURE 4. The dystrophin glycoprotein complex. Simplistic view
torn by shear forces produced during muscle con-                     of proteins involved in the dystrophin–glycoprotein complex. This
traction. Recent findings suggest that dysregula-                     shows how disruption in the muscle membrane complex can dis-
tion of the DGC mediates the development of can-                     rupt the intramuscular cytoskeleton, leading to muscle breakdown.



500    Cancer Cachexia Pathophysiology                                             HEAD & NECK—DOI 10.1002/hed            May 2007
                                                                    known to deplete the pool of myosin heavy chain,
                                                                    resulting in diminished muscle protein synthesis
                                                                    and cachexia. Thus, cytokine-mediated inhibition
                                                                    of MyoD production ultimately suppresses myosin
                                                                    heavy chain expression, preventing muscle forma-
                                                                    tion and leading to atrophy.

                                                                    Myostatin Up-regulation.     Impaired skeletal mus-
                                                                    cle anabolism is also caused by overexpression of a
                                                                    muscle gene regulator known as myostatin. Myo-
                                                                    statin is a muscle-specific negative regulator of
                                                                    skeletal muscle growth that can suppress muscle
                                                                    cell proliferation and differentiation in an NF-jB–
FIGURE 5. Down-regulation of MyoD by TNF-a and IFN-g.               independent manner.22 Muscles of tumor-bearing
TNF-a and IFN-g activate intracellular signaling pathways to in-    mice exhibit significantly higher levels of myosta-
hibit MyoD expression in an NF-jB–dependent manner. MyoD,           tin than muscles in non–tumor-bearing mice,22
myogenic differentiation gene; IFN-g, interferon gamma; IFNR,
interferon receptor; TNF-a, tumor necrosis factor alpha; TNFR,
                                                                    and transgenic mice with overexpression of the
tumor necrosis factor receptor; IjB, inhibitor of nuclear factor    myostatin gene develop a cachexia-like syndrome
kappa B; Ijj, inhibitor of nuclear factor kappa B kinase; NF-jB,    characterized by severe wasting.22 Although its
nuclear factor kappa B; p65, p65 transcription factor, a subunit    role remains to be more accurately characterized,
of nuclear factor kappa B; p55, p55 transcription factor, a subu-   myostatin up-regulation appears to be an impor-
nit of nuclear factor kappa B. [Color figure can be viewed in the
online issue, which is available at www.interscience.wiley.com.]
                                                                    tant factor in impaired muscle regeneration in
                                                                    cancer cachexia.
                                                                        To summarize, skeletal muscle atrophy in
Imbalance in the Amino Acid Ratio.     Protein syn-                 patients with cancer cachexia is characterized by
thesis in patients with cancer cachexia is                          accelerated catabolism and impaired anabolism.
impaired by an imbalance in the physiologic                         Accelerated muscle catabolism is mediated by up-
amino acid ratio. As mentioned previously, free                     regulation of the UPS proteolytic pathway, tumor
amino acids are released by the UPS following the                   release of the muscle catabolic factor PIF, and dys-
breakdown of skeletal proteins. These are then                      regulation of the DGC. Impaired muscle anabo-
taken up by the liver, where they are converted to                  lism is mediated by an imbalance in the amino
acute-phase proteins in order to meet increased                     acid pool, reduced myosin expression, and up-reg-
energy needs of chronic inflammation in cachexia.                    ulation of the muscle gene regulator myostatin.
The large amount of amino acids consumed in
skeletal muscle breakdown depletes the physio-
logic reserve of amino acids available for skeletal
                                                                    ADIPOSE TISSUE
muscle synthesis. Without the proper ratio of free
amino acids, general protein synthesis is inhib-                    Cachexia also involves abnormalities in lipid me-
ited. Thus, increased skeletal muscle breakdown                     tabolism, resulting in marked adipose tissue loss
appears to alter the free amino acid ratio, thereby                 in the cachectic patient. Indeed, body composition
inhibiting protein synthesis in skeletal muscle.                    analysis of lung cancer patients with loss of 30%
                                                                    or more of their premorbid weight showed an 85%
Reduced Expression of Myosin.     Reduced myosin                    fall in total body fat.23 Increased adipose tissue ca-
expression has also been implicated in impaired                     tabolism, rather than impaired anabolism, appears
protein anabolism in cachexia. Cachectic tumor-                     to be central to the etiology of fat loss in cachectic
bearing rats exhibit decreases in myosin expres-                    patients. This is characterized by increased lipoly-
sion that may be induced by circulating proinflam-                   sis, hypertriglyceridemia, increased hepatic secre-
matory cytokines.20 Recent studies of cultured                      tion of very low density lipoprotein, increased de
myocytes demonstrated that protein catabolism                       novo fatty acid synthesis, and a futile cycle of fatty
induced by TNF-a and IFN-g suppresses the pro-                      acids between the liver and adipose tissue. Adipose
duction of MyoD in an NF-jB–dependent manner                        tissue catabolism appears to be stimulated by a tu-
(Figure 5).21 MyoD is a muscle-specific nuclear                      mor-derived factor called lipid-mobilizing factor
transcription factor that transcribes myosin                        and by circulating proinflammatory cytokines in
heavy chain gene. Reduced MyoD expression is                        the tumor-bearing host.


Cancer Cachexia Pathophysiology                                          HEAD & NECK—DOI 10.1002/hed      May 2007    501
Lipid Mobilizing Factor.    Lipid-mobilizing factor     tivity in human adipose tissue by down-regulating
(LMF) is a 43-kDa lipolytic factor derived from         LPL protein expression.28 Increased LPL activity
both tumor and brown adipose tissue. It is homolo-      produces hyperlipidemia and prevents the storage
gous with human protein Zn-a2-glycoprotein, and         of fat, while increased LMF release stimulates the
has been isolated from the urine of both cachectic      release of FFAs from adipocytes and induces their
cancer patients and cachectic mice.24,25 It is          oxidation by uncoupling proteins. Also, TNF-a
known to cause a selective reduction in body fat,24     and IL-1 have both been shown to inhibit glucose
and is thought to be responsible for atrophy of adi-    and FFA transport into adipose tissue.29 This ulti-
pose tissue in cachectic patients. One study found      mately decreases lipogenesis in adipose tissue.
that cancer patients with weight loss had detecta-      Additionally, TNF-a has been implicated in down-
ble concentrations of LMF in their urine, while         regulating several enzymes involved in lipogene-
cancer patients without weight loss did not.26          sis, including acetyl-CoA carboxylase, fatty acid
    LMF directly stimulates lipolysis by down-reg-      synthase, and acyl-CoA synthase.29
ulating lipoprotein lipase (LPL) and up-regulat-            To summarize, the total body fat loss in pa-
ing hormone sensitive lipase.26 This results in ele-    tients with cachectic cancer is mediated primarily
vated levels of glycerol and free fatty acids (FFAs).   by increased lipolysis rather than by decreased fat
Although glycerol is cycled back to the liver to        synthesis. Increased lipolysis is a result of the
serve as a substrate for gluconeogenesis, FFAs are      actions of both LMF and TNF-a. The mechanism
taken up by cells and are used as an alternate fuel     of LMF-mediated lipolysis involves increased
source for oxidative phosphorylation and ATP pro-       expression of oxidative uncoupling proteins in
duction. Circulating FFAs are oxidized in adipose       brown adipose tissue. TNF-a inhibits LPL and
tissue by mitochondrial uncoupling proteins,            stimulates the release of lipid-mobilizing factor.
which are up-regulated by LMF. Therefore, LMF
induces accelerated FFA oxidation in brown adi-
pose tissue through up-regulation of uncoupling         INFLAMMATION
proteins, inducing fat catabolism.27 Importantly,       In addition to skeletal muscle and adipose tissue
this up-regulation of uncoupling proteins may           catabolism, cancer cachexia is characterized by a
represent the beginning of an important energy-         profound chronic inflammatory state. Inflamma-
wasting cycle. Uncoupling proteins normally             tion in cachexia has been established in a number
decrease the coupling of respiration with the phos-     of different animal models of cachexia.18 It is char-
phorylation of ADP. Their action therefore gener-       acterized by increased release of proinflammatory
ates heat instead of ATP and acts as an \energy         cytokines such as IL-1b, IL-6, TNF-a, and IFN-g.4
sink," since no ATP is produced when uncoupling         These cytokines are thought to be the principal
proteins induce protons to cross the inner mito-        catabolic factors in skeletal muscle and adipose
chondrial membrane. In a murine model of                tissue wasting in cachexia.4 These cytokines pro-
cachexia, murine adenocarcinoma 16 (MAC16)              duce many of biochemical and metabolic dysfunc-
tumors caused overexpression of uncoupling pro-         tions seen cachexia, including hypermetabolism,
tein-1 in brown adipose tissue, which resulted in       anorexia, decreased muscle protein synthesis,
increased thermogenesis, increased energy ex-           and increased UPS-mediated muscle proteoly-
penditure, and weight loss.27                           sis.18 IL-6, TNF-a, and IFN-g have been shown
    LMF therefore appears to be responsible for         to activate NF-jB, triggering UPS-mediated mus-
adipose tissue catabolism in cachexia, which it         cle breakdown and inhibiting muscle protein syn-
induces by directly stimulating lipolysis and by        thesis through reduction in MyoD expression.4
up-regulating expression of uncoupling proteins         TNF-a, on the other hand, can directly induce
in brown adipose tissue, thereby increasing fatty       lipolysis.4
acid oxidation.                                             Proinflammatory cytokines appear to potenti-
                                                        ate each other’s actions. This is seen in the activa-
                                                        tion of proteolysis (TNF-a þ IFN-g þ IL-1b) and in
Tumor Necrosis Factor-a.    TNF-a promotes fat          the up-regulation of cytokine receptors (TNF-a þ
catabolism by inhibiting fat differentiation and        IFN-g).18,30 Also, cytokines such as IFN-g, IL-1b,
increasing adipocyte apoptosis. The primary             and IL-6 are thought to be responsible for the
mechanism of TNF-a-induced fat loss in patients         induction of acute-phase protein production. To-
with cachectic cancer involves inhibition of LPL        gether, increased cytokine levels have been shown
and stimulation of LMF.4 TNF-a inhibits LPL ac-         to reduce survival time in cachectic patients.4


502   Cancer Cachexia Pathophysiology                              HEAD & NECK—DOI 10.1002/hed     May 2007
Following is a summary of the major proinflam-          Tissue Necrosis Factor-a.    TNF-a is a 17.4-kDa
matory cytokines involved in the pathogenesis of       protein produced by macrophages and natural
cancer cachexia.                                       killer cells that plays a complex and multifaceted
                                                       role in cancer cachexia. It induces proteolysis,
                                                       activates lipolysis, and suppresses expression of
Interleukin-1b.   Derived from macrophages and         enzymes involved in lipogenesis.4 TNF-a has been
lymphocytes, IL-1b concentrations increase in the      implicated in muscle wasting in several animal
cachectic state. IL-1b is thought to be partly re-     models, including the Yoshida AH-130 hepatoma
sponsible for muscle wasting in cachexia, and is       and Lewis lung carcinoma.36,37 Increased concen-
known to cause effects similar to those seen by        trations of TNF-a are seen in cancer cachexia in
TNF-a, including stimulation of muscle catabo-         humans4 and have been shown to correlate with
lism.31,32 Also, IL-1b appears to be linked to the     decreased food intake and body weight, increased
development of cachexia through the induction of       body temperature, decreased glycogen, lipid, and
the inflammatory response. In a murine model of         protein synthesis, and increased gluconeogenesis,
head and neck cancer, mice with a double muta-         lipolysis, and proteolysis.28 As mentioned pre-
tion in the Toll-like receptor-4 (TLR4) lack the       viously, TNF-a appears to suppress skeletal mus-
ability to mount an appropriate inflammatory            cle differentiation by suppressing MyoD expres-
response. In this model, wild-type cogenic mice        sion, and it can down-regulate myosin heavy
receiving injections with equal numbers of a squa-     chain in combination with IFN-g.38 Both of these
mous cell carcinoma cell line, SCCF-VII, were          occur in an NF-jB–dependent manner. TNF-a
found to be more cachectic and exhibited higher        also appears to be involved in adipocyte apoptosis,
levels of IL-1b than mutant mice (personal com-        which it induces by activating cellular proteases
munication, Marion Couch, MD, PhD). IL-1b is           known as caspases.39 Experimental treatment of
also thought to be responsible for the induction of    cachexia with the synthetic anti–TNF-a antibody
anorexia in cachectic patients. It can induce ano-     infliximab demonstrated weight stabilization in
rexia when administered to animals, and it may         1 of 4 patients with metastatic small cell lung
increase the levels of corticotrophin releasing hor-   cancer.14
mone, an anorexigenic neurotransmitter.31 IL-1b
may also increase levels of tryptophan in the cere-
brospinal fluid, increasing serotonergic neuro-
                                                       Interferon g.   IFN-g is a pleiotropic cytokine in-
transmission production in the hypothalamus and
                                                       volved in the regulation of nearly all phases of
inducing anorexia.
                                                       immune and inflammatory responses. Produced
                                                       by T lymphocytes and natural killer cells, IFN-g
Interleukin-6.  IL-6 is a glycoprotein predomi-        causes imbalance between orexigenic and ano-
nantly secreted by activated immune cells. It is       rexigenic signals in the body. As mentioned above,
involved in the amplification of inflammatory cas-       IFN-g, when administered together with TNF-a,
cades in the immune response, and its concentra-       induces UPS-mediated proteolysis in mice. It has
tions are increased in patients with cancer            also been shown to produce progressive weight
cachexia and in patients with lung cancer in           loss in mice inoculated with Lewis lung tumors.
whom IL-6 acts to enhance the acute phase              Finally, treatment with anti–IFN-g antibodies
response.33 Elevated IL-6 concentrations are cor-      counteracts this effect, indicating a potential
related with poor nutritional status, impaired per-    future treatment for cachexia.40
formance and shorter survival, indicating that the        To summarize, the proinflammatory cytokine
inflammatory response induced in part by IL-6           pathways involved in cancer cachexia are quite
may cause a substantial amount of the morbidity        complex. At this time, relatively little is known
seen in cachexia.34 IL-6 has also been implicated      about how these cytokines induce and maintain
as an important mediator of cachexia in murine         cachexia in humans. But as more is learned about
models. In BALB-C nude mice bearing colon-26           the ability of each human tumor system to induce
adenocarcinoma tumors, IL-6 is markedly over-          cachexia, the relative contribution of these cyto-
secreted.35 Robust production of IL-6 by tumor         kines to the pathogenesis of cachexia will be
cells has been shown to induce cachexia in murine      understood. A final common pathway may exist
adenocarcinoma models, and serum IL-6 levels           for all proinflammatory cytokines involved in
have been shown to be 35% higher in cachectic          cachexia. This might ultimately become an ave-
mice than in noncachectic mice.4                       nue for future treatment.


Cancer Cachexia Pathophysiology                             HEAD & NECK—DOI 10.1002/hed    May 2007    503
ANABOLIC HORMONE DYSREGULATION                          proinflammatory cytokines implicated in cachexia
In normal adults, bone growth and tissue mainte-        can produce chronic leptin up-regulation, result-
nance rely on an intact growth hormone (GH)/in-         ing in increased anorexia.45 Although elevated
sulin-like growth factor-1 (IGF-1) axis. There is       leptin has been found in patients with cachectic
mounting evidence that patients with cachexia           cancer, low levels of leptin have been found in ca-
may have alterations in this axis.18 Acquired GH        chectic mice. In MAC16-tumor-bearing mice, for
resistance has been reported, but the role of the       example, circulating leptin levels were signifi-
GH/IGF-1 axis in catabolic states such as cancer        cantly reduced.46 This indicates that leptin may
cachexia has not been adequately characterized.41       not consistently mediate cachexia, and that tumor
Administering GH as part of an acute therapy for        products such as LMF and PIF are able to override
ICU patients has been shown to cause increased          the effects of low levels of leptin and independ-
mortality.42 Therefore, more research is needed         ently cause appetite suppression and cachexia.46
before GH or IGF-1 can be considered as a possible      From the above evidence, we conclude that the
therapy for wasting.                                    true role of leptin has not been accurately charac-
                                                        terized. It is unclear at this point whether leptin
                                                        plays a leading role in the development of ano-
NEUROENDOCRINE DYSFUNCTION                              rexia in cancer cachexia, or if it is overridden by
Patients with cancer frequently suffer from ano-        tumor-derived factors (Figure 6).
rexia. The prevalence of anorexia in cachectic
patients may range between 15% and 40% at pre-          Ghrelin.  Ghrelin is a novel GH-releasing pep-
sentation.43 This may be an effect of the tumor         tide that was first isolated from the stomach.
itself or the consequence of treatments such as         Secreted from the stomach, it stimulates food
chemotherapy and radiation. It appears that ano-        intake and decreases energy expenditure, thereby
rexia is a consequence of weight loss, rather than      increasing body weight. Ghrelin circulates in the
its cause, since reduced food intake in cachectic       bloodstream under fasting conditions and trans-
patients is preceded by tissue wasting.44 The           mits a hunger signal from the periphery to the
mechanisms of appetite dysregulation in cancer          CNS, where it acts directly to increase feeding
cachexia appear to involve disrupted communica-         and decrease sympathetic nerve activity. Ghrelin
tion between peripheral organs and homeostatic          appears to act as a counterpart to leptin, which
control centers in the hypothalamus. Neuroendo-         decreases feeding and increases sympathetic
crine afferent signals originating from peripheral      nerve activities. Indeed, cancer cachexia involves
organs inform the brain about nutritional require-      inordinately increased levels of active ghrelin.47
ments and energy status. In the healthy patient,        This may be a compensatory response to marked
peripheral nutritional signals are integrated and       weight loss in the cachectic patient.
processed within homeostatic control centers in
the hypothalamus and an appropriate response is         Neuropeptide Y.     NPY is an orexigenic neuro-
communicated via efferent pathways back to pe-          transmitter that is involved in regulation of circa-
ripheral organs. In the cachectic patient, however,     dian rhythms, sexual functioning, anxiety, pe-
disruption within this signaling system results in      ripheral vascular resistance and cardiac contrac-
anorexia and reduced food intake. Three neuro-          tility. Although widely distributed throughout the
peptide mediators of this signaling pathway, lep-       brain, it is found abundantly in the arcuate nu-
tin, ghrelin, and neuropeptide Y (NPY), are             cleus of the hypothalamus. A potent feeding-stim-
believed to be responsible for the disruption of this   ulatory peptide, NPY has been shown to reverse
feedback loop in cachectic patients.

Leptin.   A product of the ob gene, leptin is a neu-
roendocrine hormone secreted by adipose tissue.
It has anorectic and lipolytic properties and is
known to regulate weight by inhibiting feeding. In
normal patients, weight loss lowers leptin levels,
triggering the hypothalamus to stimulate feeding.
                                                        FIGURE 6. Leptin dysregulation in adipose tissue. Loss of fat
In most experimental models of cachexia, how-           mass in normal weight loss leads to a drop in leptin levels,
ever, leptin levels are elevated. This results in in-   removing the inhibitory effect of leptin on appetite. In cachexia,
hibition of orexigenic signals. Indeed, some of the     elevated leptin levels inappropriately inhibit food intake.



504   Cancer Cachexia Pathophysiology                                 HEAD & NECK—DOI 10.1002/hed             May 2007
FIGURE 7. Summary of the pathophysiology of cancer cachexia. UPS, ubiquitin–proteasome system; DGC, dystrophin glycoprotein
complex; A.A., amino acid; MSTN, myostatin; LMF, lipid mobilizing factor; NPY, Neuropeptide Y.




anorexia induced by the proinflammatory cyto-                    traceutical or pharmacologic intervention to blunt
kines IL-1b and ciliary neurotrophic factor.48                  inflammation and improve food intake.
However, it has also been found to be dysfunc-
tional in anorectic tumor-bearing rodents, making
it a possible mediator of cancer cachexia in hu-                Cancer Cachexia: An Autoimmune Disease?      Finally,
mans (Figure 7).                                                not all tumors are the same, and all hosts are
                                                                physiologically different. Certain tumors may
                                                                secrete more catabolic factors or induce a more
                                                                exaggerated inflammatory response in their hosts
NEW CONCEPTS                                                    than other tumors. However, given the same tu-
                                                                mor type and burden, why do some patients with
Cancer Cachexia and Aging.     As natural conse-                cancer develop cachexia while others do not? We
quences of aging, patients with head and neck                   propose that there may be single nucleotide poly-
cancer often experience sarcopenia, physical inac-              morphisms in a variety of important immune
tivity, and reduced protein regeneration. Their                 receptors that may predispose certain patients to
sarcopenia from aging may be due to down-regula-                develop cachexia. The presence of such polymor-
tion of the growth hormone axis and decline in tes-             phisms might explain the interindividual differ-
tosterone concentrations, while their physical                  ences seen in the clinical manifestations of
inactivity may be multifactorial and their im-                  cachexia.
paired protein synthesis a result of resistance to                  One set of candidates for this genetic variabili-
muscle-specific anabolic signals. Patients with ca-              ty is the family of Toll-like receptors (TLRs). These
chectic head and neck cancer suffer from systemic               cell-surface receptors are involved in immune reg-
inflammation and reduced food intake in addition                 ulation and mediate both sterile and infectious
to these aging-related processes. Therefore, treat-             inflammatory responses and the complex
ment of patients with cachectic cancer requires                 responses involved in autoimmunity. Their stimu-
a multipronged, multidisciplinary approach.41                   lation produces a robust cytokine response, which
Treatment plans should incorporate physical                     includes elaboration of IL-1b, IL-6, TNF-a, and
therapy to improve mobilization, high protein                   IFN-g. Ten TLR paralogs have been identified in
intake to maximize muscle anabolism, and neu-                   humans, which together recognize exogenous mol-


Cancer Cachexia Pathophysiology                                       HEAD & NECK—DOI 10.1002/hed         May 2007     505
ecules from a diverse array of organisms, including        Finally, new concepts are evolving in this field.
bacteria, fungi, and viruses. TLRs also recognize      These include the role of aging in cancer cachexia
the important and widely distributed lipopolysac-      and the role of TLR gene polymorphisms in alter-
charide (LPS) molecules on bacteria. Interestingly,    ing responses to the cachectic state. We hope fur-
LPS injection into mice produces wasting similar       ther research into these areas will answer remain-
to cancer cachexia.49 Mice with double mutations       ing questions about the underlying mechanisms
in the TLR gene are actually resistant to the devel-   of cachexia.
opment of such wasting, while their wild-type
counterparts are not.49 Furthermore, such mutant       Acknowledgments. We thank Dr. Anne Voss,
mice exhibit lower levels of IL-1b and are signifi-     Senior Research Scientist, Abbott Laboratories,
cantly less cachectic after SCCF VII tumor chal-       Inc and Corey Cannon for artistic contributions.
lenge than their wild-type counterparts, as meas-
ured by weight and body composition.41
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Cancer Cachexia Pathophysiology                                           HEAD & NECK—DOI 10.1002/hed           May 2007       507

								
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