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Signal transduction in tumor cachexia

 

The mechanisms responsible for tumor cachexia are poorly understood to date. However, this syndrome is always associated with a poor prognosis and is characterized by complex metabolic alterations including atrophy of skeletal muscle. The increased catabolism in these tissues and a systemic inflammatory response suggest that the pro-inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) participate in signalling pathways responsible for cachexia. Cancer related wasting of muscle tissue may be either due to decreased protein synthesis or increased protein degradation, but the understanding of the molecular mechanisms in particular is at the pole position. A central role for muscular growth regulation in animal models plays the phosphatidylinositol 3-kinase (PI3-K)/Akt signalling pathway. This anabolic signal transduction is activated by the binding of insulin / insulin-like growth factor 1 (IGF-1) to the corresponding receptors, catalyzing the phosphorylation of insulin receptor substrate protein 1 (IRS1), which serves as a docking site for the p85 regulatory subunit of PI3-K, leading to phosphatidylinositol –3,4,5-triphosphate (PIP3) generation, activation of serine/threonine kinase Akt (PKB) and mammalian target of rapamycin (mTOR), as well as p70S6 kinase, which stimulates protein synthesis. Moreover, phosphorylation and inhibition of the pro-apoptotic Forkhead O (Foxo) group (Foxo1 and Foxo3a) was found to increase the expression of the ubiquitin-ligases MAFbx and MuRF1. Thus, inhibition of the PI3-K/Akt pathway leading to proteasome activation seems to be a hallmark of muscle wasting.

 

The experiments include investigations in vitro, as well as muscle biopsies from mice models and clinical studies to understand fundamental mechanisms of cachexia signalling in muscle cells.

 

Current Projects include:

  • Analyzing the molecular mechanisms by which Akt/mTOR/ p70S6 kinase/Foxo and other key players mediates signalling during cachexia.
  • Studying drugs that are on the horizon to antagonize tumor cachexia in vitro and in vivo.
  • Functional analysis of Akt/mTOR/ p70S6 kinase/Foxo effector functions.

 

Please contact PD Dr. Wulf Hildebrandt for further information:        
wulf.hildebrandt@staff.uni-marburg.de


 

Key Publications

Weber MA, Krakowski-Roosen H, Schroder L, Kinscherf R, Krix M, Kopp-Schneider A, Essig M,
          Bachert P, Kauczor HU, Hildebrandt W. Morphology, metabolism, microcirculation, and strength
          of skeletal muscles in cancer-related cachexia. Acta Oncol. 2009; 48(1):116-24.

Weber MA, Hildebrandt W, Schröder L, Kinscherf R, Krix M, Bachert P, Delorme S, Essig M,
          Kauczor HU, Krakowski-Roosen H. Concentric resistance training increases muscle strength

          without affecting microcirculation. Eur J Radiol. 2010 Mar;73(3):614-21.

Martignoni ME, Dimitriu C, Bachmann J, Krakowski-Rosen H, Ketterer K, Kinscherf R, Friess
          H. Liver macrophages contribute to pancreatic cancer-related cachexia. Oncol Rep. 2009
          Feb;21(2):363-9.

Weber MA, Kinscherf R, Krakowski-Rosen H, Aulmann M, Renk H, Künkele A, Edler L,
         
Kauczor HU, Hildebrandt W Myoglobin plasma level related to muscle mass and fiber
         
composition - a clinical marker of muscle wasting ? J Mol Med 2007; 85(8):887-96.

Weber MA, Krakowski-Rosen H, Hildebrandt W, Schröder L, Ionescu I, Krix, M, Kinscherf R,
         
Bachert P, Kauczor HU, Essig M. Assessment of Metabolism and Microcirculation of Healthy
         
Skeletal Muscles by Functional Magnetic Resonance and Ultrasound Techniques. J Neuro-
          imaging
2007; 17(4):323-31.

Schmitt TL, Martignoni ME, Bachmann J, Fechtner K, Friess H, Kinscherf R, Hildebrandt W
         
Activity of the Akt-dependent anabolic and catabolic pathways in muscle and liver
         
samples in cancer-related cachexia. J Mol Med 2007; 85(6):647-54.

Holm E, Hildebrandt W, Kinscherf R, Dröge W. Low absorptive net protein degradation in male
          cancer patients: Lack of sensitivity to regulatory amino acids? Oncology Reports 2007; 17:
          695-700.

Weber MA, Krakowski-Rosen H, Delorme S, Renk H, Krix M, Millies J, Kinscherf R, Künkele
          A, Kauczor HU, Hildebrandt W. Relation of skeletal muscle perfusion measured by
          contrast-enhanced ultrasound to histological microvascular density. J Ultrasound Med 2006
          25(5):583-91.

Hildebrandt W, Hahmann A, Krakowski-Roosen H, Kinscherf R, Dugi K, Sauer R, Lacher S,
          Nöbel N, Bodens A, Bellou V, Edler L, Bärtsch P, Nawroth P, Dröge W Effect of thiol antioxidant
          on body fat and insulin reactivity. J Mol Med 2004; 82: 336-344.

Hildebrandt W, Kinscherf R, Hauer K, Holm E, Dröge W. Plasma cystine concen tration and redox
          state in ageing and physical exercise. Mechanism Aging Dev 2002; 123 (9): 1269-1281.

Hack V, Breitkreutz R, Kinscherf R, Röhrer H, Bärtsch P, Taut F, Edler L, Dröge W.
          The redox state as a correlate of senescence and wasting and as a target for therapeutic
          intervention. Blood 1998; 92: 59-67.

Hack V, Schmid D, Breitkreuz R, Stahl-Hennig C, Drings P, Kinscherf R, Taut F, Holm E, Dröge W.
          Cystine levels, cystine flux and protein catabolism in cancer cachexia, HIV/SIV infection, and
          senescence. FASEB J 1997; 11: 84-92.

Hack V, Stütz O, Kinscherf R, Schykowski M, Kellerer M, Holm E, Dröge W. Elevated venous
          glutamate levels in (pre)catabolic conditions result at least partly from decreased glutamate
          transport activity. J Mol Med 1996; 74: 337 – 343.

Hack V, Groß A, Kinscherf R, Bockstette M, Fiers W, Berke G, Dröge W. Abnormal glutathione and
          sulfate levels after interleukin-6 treatment and in tumor- induced cachexia. FASEB J 1996;
          10: 1219 – 1226.

 

Zuletzt aktualisiert: 07.06.2013 · posth

 
 
 
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