Hyperactivation of the TGF-? signaling pathway in glioblastoma: mechanisms and consequences

• Autores: Laura Rodón Ahnert
• Directores de la Tesis: Joan Seoane Suarez (dir. tes.)
• Lectura: En la Universitat de Barcelona ( España ) en 2012
• Idioma: inglés
• Tribunal Calificador de la Tesis: Carme Caelles Franch (presid.), Maria Isabel Fabregat Romero (secret.), Salvador Aznar Benitah (voc.)
• Materias:
  • Ciencias médicas
    • Ciencias clínicas
      • Oncología
    • Patología
      • Carcinogénesis
      • Oncología
• Enlaces
  • Tesis en acceso abierto en:  TDX  Dipòsit Digital de la UB 
• Resumen

  • The TGF-? pathway is currently considered a therapeutic target in advanced tumors, including glioblastoma (GBM), and several anti-TGF? agents are in clinical trials and have shown promising results .A thorough understanding of the molecular mechanisms involved in the protumorigenic function of TGF-? will facilitate the identification of markers of response that can be used to stratify patients to be treated with anti-TGF? compounds and, moreover, will allow for the discovery of new therapeutic agents. TGF-? is highly active in high-grade glioma, and elevated TGF-? activity confers poor prognosis. Aberrant activation of TGF-? is caused in part by enhanced secretion of the TGF-? ligands by tumor cells and tumor stroma cells. However, the precise mechanisms that lead to the hyperactivation of the TGF-? pathway are not yet fully understood. In this work, we have demonstrated that the TGF-? signaling pathway can be hyperactivated in GBM by different means including the stabilization of the T?RI by overexpression of the deubiquitinating enzyme USP15 or the enhanced secretion of TGF-?2 by the generation of a malignant autocrine loop via CREB. In this project, we identified USP15 and CREB as two novel regulators of TGF-? activity. USP15 and CREB could be considered as markers of response to anti–TGF-? molecules and potential therapeutic targets against GBM.