Understanding Cachexia: a major complication of cancer

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Understanding Cachexia a major complication of
cancer

• Pattarana Sae-Chew, Ph.D.

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What is Cachexia?

• Cachexia (Greek Kachexia Kakoexis) or Muscle
  wasting
• Severe, chronic, unintentional, and progressive
  weight loss
• Loss of adipose tissue and lean body mass
• Visceral protein preserved
• chronic diseases
• Congestive Heart Failure
• Acquired Immunodeficiency Syndrome
• Chronic Malaria
• Rheumatoid Arthritis
• Chronic Obstructive Pulmonary Disease
• Cancer

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Metabolic alterations in Cachexia

• Anorexia Loss of Appetite
• Early satiety
• Anemia
• Lypolysis
• Resting energy expenditure
• Activation of acute phase response
• Insulin resistance

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Clinical Definition

• In 2006, Fearon KC., et al. proposed definition
  for cancer cachexia
• Body weight loss 10
• Nutrient intake 1,500 kcal/day
• Level of C-reactive protein 10mg/L
• Advantages
• Strong clinically and pathophysiologically
  supported
• Prognostically validated
• Based on objective criteria

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Clinical Definition

• In 2006, Fearon KC., et al. proposed definition
  for cancer cachexia
• Body weight loss 10
• Nutrient intake 1,500 kcal/day
• Level of C-reactive protein 10mg/L
• Limitations
• Does not classify cachexia
• Difficulty in accessing calorie intake for
  out-pateint

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Cachexia vs. Starvation

• Starvation depletes fat stores from adipose
  tissue while conserving protein from skeletal
  muscle
• Nutrition supplements for cachexia treatment
• Promote weight gain due to the replenishment of
  fat
• Ineffective to restore skeletal muscle protein
  content

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Public Health Significance

• Cancer-cachexia
• Debilitating life threatening
• 5 millions U.S. (in Thailand???)
• Poor prognosis, quality of life
• Increase patient susceptibility
• No effective treatment
• High public health cost
• Personal family suffering

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Cancer-cachexia incidence

• Laviano A., et al. Nat Clin Pract Oncol. 2005
  Mar2(3)

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Consequences of wasting

• Muscle fiber size and protein content
• Force and power output
• Fatigue
• Asthenia Prognosis, response to therapy,
  Quality of life
• Immobility
• Cardiac or respiratory failure 20 mortality

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Muscle fiber size in cachexia
Non-tumor-bearing
c26-tumor-bearing
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Consequences of wasting

• Muscle fiber size and protein content
• Force and power output
• Fatigue
• Asthenia Prognosis, response to therapy,
  Quality of life
• Immobility
• Cardiac or respiratory failure 20 mortality

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Underlying mechanism

• Exact mechanism ? ????
• proinflammatory cytokines
• TNF-a
• IL-1
• IL-6
• IFN-g

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Cytokines as cachexia mediator
Diseased group A healthy control B
patients w organ-confined CaP C patients w
advanced CaP Ca noncachectic advanced CaP
Cb cachectic advanced CaP

• Pfitzenmaier J et al. Cancer. (2003)

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Cytokine vs. BMI
Kuroda K., et al. Clin Cancer Res. (2005)
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Cytokines and Cachexia

• Stephens NA, Curr Opin Support Palliat Care.
  2008 Dec2(4)267-74.

240
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Proteolysis

• Ubiquitin-Proteasome System (UPS)

Muscle-specific E3 MuRF1, MAF/bx
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Cytokines-induced muscle protein degradation
TNF-a
Cytoplasm
26S proteasome
Nucleus
NF-kB target genes
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Activation of NF-kB

• Nuclear factor kB (NF-kB) Signaling pathway
• TNF-a activation of NF-kB pathway in muscle
  wasting conditions during disease states
• Required for muscle degradation
• Inhibits skeletal myogenesis in vitro

Tada K., et al. J Biol Chem. 2001 Sep 28276(39)
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TNF-a promotes myofibrillar proteins loss
Guttridge DC., et al. Science. 2000
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Cytokines-induced muscle protein degradation

• 
  Ubiquitin-Proteasome
• Cytokines NF-kB
• 
  
• MyoD, myogenin
• 
  MyHC
• Activation
• Inhibition

20S, MuRF1, MAF/bx
YY1
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Cytokines and Cachexia

• Stephens NA, Curr Opin Support Palliat Care.
  2008 Dec2(4)267-74.

60
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Depression of protein synthesis
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Depression of protein synthesis
PIF, Ang II
e-IF2a
PKR
p-PKR
p-e-IF2a
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Depression of protein synthesis
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Depression of protein synthesis
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Depression of protein synthesis
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Protein translation factors in cachexia
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Treatment for Cachexia

• Most effective ?Treat diseases origin of
  cachexia
• AIDS
• Cancer
• Congestive Heart Failure
• COPD

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Pre-clinical study

• Effect of Branched-Chain Amino Acids on Muscle
  Atrophy in Cancer Cachexia, Helen L. Eley, Steven
  T. Russell, and Michael J. Tisdale
• 
  Biochem. J.
  Oct. 2007

Val
Leu
PBS
Ile
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Pre-clinical study

• Amelioration of Cancer-Induced Cachexia by
  Inhibition of
• NF-kB Signaling Pathway, Pattarana Sae-Chew and
  Paula R. Clemens

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Treatment for Cachexia
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Treatment for Cachexia
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Cancer in Thailand
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Cancer in Thailand
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Cancer in Thailand
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Cachexia in Thailand

• Where are we ???????

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QAComments

• Thank you

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Skeletal Muscle Differentiation

• Mesodermal Myoblast
  Multinucleated
  Mature
• progenitor
  myotube
  myotube

Pax3 Pax7 MyoD
Myogenin
Myf5
MRF4

MHC

MCK
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Introduction

• During skeletal differentiation
• Myogenic bHLH transcription factor family
• MyoD, Myf5, myogenin, MRF-4, and the MEF-2 family
  of transcription factors
• Is activated and followed by terminal cell cycle
  arrest
• Regulate the late phase of myogenesis by inducing
  the expression of myofibrillar protein such as
  MHC
• Ultimately leads to the fusion of myoblasts into
  mutinucleated myotubes

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Introduction