7 - Metabolic Stress in Cancer, Cachexia

Question 1

Cachexia

Answer 1

• “Wasting Syndrome”
  
  • Unintentional loss of body weight / mass
  • Loss of appetite / energy
• ​Unrelated to tumor size or state
  
  • Small Tumors of Pancreas –> MORE wasting

Question 2

Cancer Associated Cachexia

CAC

Answer 2

• CAC
  
  • -> Reduce the # of CHEMOTHERAPY cycles ​that can be completed
  • Increase complications w/ cancer
• ​Common at the end of life in cancer patients​

Question 3

Cytokine - TNF-alpha in Cachexia

Answer 3

• One cytokine that was related to body weight loss
  
  • was released after injection of tumor-activated macrophages
    
    • these macrophages released TNF-alpha
    • Host-tumor response

Question 4

How do TUMORS cause CAC?

Answer 4

• @Tissue level, tumors have:
  
  • tumor cells
  • cancer associated Fibroblast
  • Immune cells
    
    • -> secrete a variety of cytokines SYSTEMICALLY
      
      • Alter metabolism everywhere
        
        • ​–> CACHEXIA

Question 5

What represents the main predictor of mortality?

Answer 5

• Weight Loss from Cachexia
  
  • Multi-factoral, caused by:
    
    • Reduced food intake
    • systemic metabolic dysfunction
    • INCREASE in Energy expenditure

Question 6

What causes WEIGHT LOSS in cancer?

Answer 6

Reduced food intake

systemic metabolic dysfunction

INCREASE in Energy expenditure

• ​Experiment: injecting TNF-Alpha or IL6 in mice
  
  • Caused weight loss
  • but the same number of cancer cells did NOT
    
    • ​_ultimately it’s the response that causes weight loss / cachexia_

Question 7

How does Cancer cause CACHEXIA?

Answer 7

• Absorptive Disorders
• Reduced Intake
  
  • Cancer treatments -> Anorexia
  • • decrease in physical activity & mechanical obstacles
• Metabolic Disturbances
  
  • ​Host/tumor competitions + Tumor side products:
    
    • Inadequation
    • Metabolism

Question 8

CAC & Glucose metabolism

Answer 8

• Glucose levels clear FASTER
• Glucose production is also INCREASED due to:
  
  • Cori Cycle
    
    • ​Lactate Dehydrogenase (LDH) is massively INCREASED
      
      • in liver:
        
        • pyruvate –> LACTATE excess

Question 9

CAC & Lipolysis

Answer 9

• Tumor secreting:
  
  • TNF-alpha
  • IL6
  • Prostaglandins
    
    • ​–> I_NCREASED LIPOLYSIS_
      
      • in Adipose, TG’s -> FFA’s + Glycerol

Question 10

CAC & Adipocytes

Answer 10

• Change in mitochondrial content:
  
  • WAT -> Brown Adipose
    
    • PROMOTES Energy Expenditure
    • Body weight loss
• ​​Browning occurs before the loss of skeletal mass

Question 11

How does WAT Browning Occur?

Answer 11

• IL-6 + PTHrP (parathyroid hormone related protein)
  
  • ​induces changes in UCP1
    
    • ​–> INCREASE in Mitochondrial Content​
      
      • ​decreased lipogenesis
      • Increased Lipolysis
        
        • WAT –> BROWN ADIPOCYTES

Question 12

What does Brown Adipocytes do to the body?

Answer 12

• BAT’s go from energy storage –> PRODUCTION OF HEAT
  
  • ​@Tissue level
    
    • ​Increase in Lipolysis
      
      • TG’s -> FFA + Glycerol
  • @Organismal Level
    
    • ​DANGEROUS REDUCTION IN BODY WEIGHT

Question 13

IL-6 & PTHrP

Answer 13

• Secreted from TUMOR
  
  • -> WAT
    
    • Beta adrenergic activation
      
      • ​Change UCP1 -> CHANGE IN MITO ACTIVITY
        
        • -> more LIPOLYSIS
        • -> THERMOGENESIS
          
          • -> CACHEXIA

Question 14

How does CAC cause Muscle Atrophy?

Answer 14

• The TGF-Beta superfamily members:
  
  • Myostatin + Activin
    
    • -> signal ACTR2B (activin type 2 receptor - B)
      
      • ATROPHY OF MUSCLES (including heart)

Question 15

Myostatin and Activin

Answer 15

TGF-Beta superfamily members

Signal ACTR2B

and cause MUSCLE ATROPHY

ARE OVERACTIVE IN CAC PATIENTS

Question 16

What does the BLOCKADE of ACTR2B cause?

Answer 16

• Reduce Muscle Atrophy*
• Prevents Atrophy of Cardiac Muscle*

Positive influence on Insulin Resistance

& Systemic Inflammation

Tested on MICE

Question 17

What does a ACTR2B INHIBITOR do?

Answer 17

• Negatively influences Myostatin + Activin
  
  • ​so they do not activate ACTR2B
    
    • -> Hypertrophy signals occur –> Build Muscle
      
      • ​Atrophy is lessened

Question 18

How does a ACTR2B ANTAGNIST affect OBESITY?

Answer 18

• ACTR2B Antagonist –> HYPERTROPHY = MORE MUSCLE
  
  • -> Less Fat
  • -> More glucose uptake
  • -> More Insulin sensitivity

Question 19

How does CAC affect the LIVER?

Answer 19

• Activated Macrophages in liver produce IL6
  
  • ​Reduction in Hepatic Oxidation
    
    • ​Increase in ROS
    • Energy Wasting
  • Increase in Hepatic Gluconeogenesis

Question 20

How CAC affects each organ’s metabolism

Answer 20

• Tumor secretes: TNF-alpha + IL6/1 -> Systemic Inflammation
  
  • ​​​Tumor + Cytokines -> Anorexia
  • ​Adipocytes
    
    • WAT -> BAT
      
      • increase in THERMOGENESIS / LIPOLYSIS
  • Liver
    
    • ​reduction in drug clearance (less oxidation)
      
      • -> increase in TOXICITY
  • Muscle Wasting
  • Adipocyte Depletion

Question 21

Ghrelin for CAC

Answer 21

• Beneficial Effect on WEIGHT GAIN (from increased APPITITE)
  
  • ​+No effect on tumor growth
• ​ANAMORELIN

Question 22

Anamorelin

Answer 22

• Non-peptide, orally active Ghrelin Receptor Agonist
• Romana 1 / 2 trials showed this in non-small cell lung cancer:
  
  • increase in Lean Body Mass
    
    • good for CAC’s weight loss issue
  • no increase in Handgrip strength
    
    • ​**to see if Anemorelin also helped with CAC’s **muscle wasting

Question 23

Possible Treatments for CAC

Answer 23

INHIBIN AGONIST (inhibit ACTR2B)

Ghrelin Receptor Agonist

ACTR2B Antagonist

Anti-inflammatories

Hormones