Understanding Cachexia: a major complication of cancer

1. Understanding Cachexia: a major complication of cancer PattaranaSae-Chew, Ph.D.

2. What is Cachexia? • Cachexia (Greek: Kachexi’a; Kako+e’xis) 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

3. Metabolic alterations in Cachexia • Anorexia: Loss of Appetite • Early satiety • Anemia • Lypolysis • Resting energy expenditure • Activation of acute phase response • Insulin resistance

4. 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

5. 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

6. 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

7. 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

8. Cancer-cachexia incidence Laviano A., et al. Nat ClinPractOncol. 2005 Mar;2(3)

9. 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

10. Muscle fiber size in cachexia Non-tumor-bearing c26-tumor-bearing

11. 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

12. Underlying mechanism • Exact mechanism  ???? • proinflammatory cytokines • TNF-a • IL-1 • IL-6 • IFN-g

13. Cytokines as cachexia mediator Pfitzenmaier J et al. Cancer. (2003) Diseased group: A = healthy control B = patients w organ-confined CaP C = patients w advanced CaP Ca = noncachectic advanced CaP Cb = cachectic advanced CaP

14. Cytokine vs. BMI Kuroda K., et al. Clin Cancer Res. (2005)

15. Cytokines and Cachexia Stephens NA, CurrOpin Support Palliat Care. 2008Dec;2(4):267-74. 240%

16. Proteolysis • Ubiquitin-Proteasome System (UPS) Muscle-specific E3: MuRF1, MAF/bx

17. Cytokines-induced muscle protein degradation TNF-a g b a Cytoplasm IKK complex TRADD RIP IkB-a Ub K63 TRAF2 p50 p65 P P P P IkB-a IkB-a p50 p50 p65 p65 Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub Ub P P P P Ub K48 P 26S proteasome Nucleus NF-kB target genes

18. 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 28;276(39)

19. TNF-a promotes myofibrillar proteins loss Guttridge DC., et al. Science. 2000

20. Cytokines-induced muscle protein degradation Ubiquitin-Proteasome CytokinesNF-kB MyoD, myogenin MyHC = Activation = Inhibition 20S, MuRF1, MAF/bx YY1

21. Cytokines and Cachexia Stephens NA, CurrOpin Support Palliat Care. 2008Dec;2(4):267-74. 60%

22. Depression of protein synthesis

23. Depression of protein synthesis Inhibition of translation initiation PIF, Ang II e-IF2a PKR p-PKR p-e-IF2a

24. Depression of protein synthesis

25. Depression of protein synthesis

26. Depression of protein synthesis

27. Protein translation factors in cachexia

28. Treatment for Cachexia • Most effective “Treat diseases origin of cachexia” • AIDS • Cancer • Congestive Heart Failure • COPD

29. 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 Ile PBS

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

31. Treatment for Cachexia

32. Treatment for Cachexia

33. Cancer in Thailand

34. Cancer in Thailand

35. Cancer in Thailand

36. Cachexia in Thailand Where are we ???????

37. Q&AComments Thank you

38. Skeletal Muscle Differentiation Mesodermal Myoblast Multinucleated Mature progenitor myotubemyotube Pax3 Pax7 MyoD Myogenin Myf5 MRF4 MHC MCK

39. 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

40. Introduction Stephens NA., et al. CurrOpin Support Palliat Care 2008, 2:267–274