Vidali 2015 Abstract MiP2015

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Alterations of the OXPHOS system in rhabdomyosarcomas.

Link:

Feichtinger RG, Vidali S, Hauser-Kronberger C, Ridzewski R, Hahn H, Kofler B (2015)

Event: MiP2015

Rhabdomyosarcoma (RMS) is an aggressive neoplasm characterized by metastatic invasion and rapid growth. This type of tumor does not only involve muscle, but also many other tissues with consequently different clinical presentations. There are three main types of RMS: alveolar, embryonal and pleomorphic. Although in the last years the survival of patients affected by RMS substantially improved, many patients still die from advanced disease [1,2]. Many tumors present a shift of the cellular metabolism from oxidative phosphorylation (OXPHOS) to aerobic glycolysis (Warburg effect) frequently caused by defects in one or more respiratory complexes [3]. The aim of the present study was to investigate whether RMS present alterations in the OXPHOS.

Formalin fixed paraffin-embedded (FFPE) tissue samples from 27 human RMS were stained for porin and complex I to V of the OXPHOS. The intensity of the immunohistochemical (IHC) staining of the proteins was evaluated and compared to normal muscle. Frozen samples of RMS (n=3) were analyzed for enzymatic activity of citrate synthase and OXPHOS complexes I to V. The results were compared to normal skeletal muscle from healthy patients (n=10-28). Transgenic mice expressing a constitutively active Hedgehog (Hh) receptor (Patched, Ptch) develop RMS [4]. Mice were treated with different Hh signaling inhibitors to investigate if these compounds could stimulate or reverse the Warburg effect in the RMS. Hh inhibitors were given either locally or systemically.

Citrate synthase activity, as well as the activity of all OXPHOS complexes, was low in the RMS samples (n=3). IHC analysis of the human RMS revealed that the immunoreactivity of porin was unchanged compared to normal adjacent muscle tissue (n=27). On the contrary, compared to control muscle, specific and significantly lower complex I levels were observed, whereas the amount of the other complexes was similar to unaffected muscle. Only embryonal RMS (ERMS) presented in addition very low complex II levels.

RMSs developed by Ptch+/- mice present many features of human ERMS, among which is also a significantly lower expression of complex I and II, compared to the normal adjacent muscle. Treatment of Ptch+/- mice with Hh inhibitors was not able to alter the OXPHOS system.

In summary RMS are characterized by a normal mitochondrial mass with an isolated complex I deficiency, ERMS also with a complex II deficiency. The low activity of the citrate synthase and the OXPHOS complexes compared to normal adjacent muscle can be explained by the high abundance of stroma/connective tissue. In addition, RMS showed a very small cytoplasm with a very limited space for mitochondria.

Ptch inhibition does not affect OXPHOS protein expression, suggesting that the Ptch receptor in RMS is not involved in the regulation of the Warburg effect, or that RMS cells present other parallel pathways that can overcome the inhibition of the Ptch+/- pathway.


O2k-Network Lab: AT Salzburg Sperl W


Labels: MiParea: Respiration, Genetic knockout;overexpression, Comparative MiP;environmental MiP, Patients  Pathology: Cancer 

Organism: Human, Mouse  Tissue;cell: Skeletal muscle 

Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase 



Event: A2, Poster, P-flash  MiP2015 

Affiliations

1-Research Program Receptor Biochem Tumor Metabolism, Dept Pediatrics, Paracelsus Medical Univ, Salzburg, Austria; 2-Dept Pathology, Paracelsus Medical Univ, Salzburg, Austria; 3-Inst Human Genetics, Univ Med Center, Goettingen, Germany. - s.vidali@salk.at

References and acknowledgements

  1. Pharm DM, Barr FG (2013) Classification of rhabdomyosarcoma and its molecular basis. Adv Anat Pathol 20:387-97.
  2. Hettmer S, Li Z, Billin AN, Barr FG, Cornelison DD, Ehrlich AR, Guttridge DC, Hayes-Jordan A, Helman LJ, Houghton PJ, Khan J, Langenau DM, Linardic CM, Pal R, Partridge TA, Pavlath GK, Rota R, Schäfer BW, Shipley J, Stillman B, Wexler LH, Wagers AJ, Keller C (2014) Rhabdomyosarcoma: Current challenges and their implications for developing therapies. Cold Spring Harb Perspect Med 4:a025650.
  3. Warburg O (1931) The metabolism of tumors. New York: Richard R Smith 1931:129-69.
  4. Uhmann A, Niemann H, Lammering B, Henkel C, Heß I, Rosenberger A, Dullin C, Schraepler A, Schulz-Schaeffer W, Hahn H (2012) Calcitriol inhibits hedgehog signaling and induces vitamin d receptor signaling and differentiation in the patched mouse model of embryonal rhabdomyosarcoma. Sarcoma 2012:357040.

This work was supported by the Children´s Cancer Foundation Salzburg, Cancer Foundation Salzburg, and the Marie Curie International Training Network MEET (317433) of the European Union.