Role of p38γ and p38δ in fibroblasts in the connection between inflammation and colon cancer

• Autores: José Martín Gómez
• Directores de la Tesis: Ana Cuenda Méndez (dir. tes.), Juan José Sanz Ezquerro (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2023
• Idioma: español
• Número de páginas: 179
• Títulos paralelos:
  • Papel de p38γ y p38δ en fibroblastos en la conexión entre la inflamación y el cáncer de colon
• Tribunal Calificador de la Tesis: Maria Almudena Porras Gallo (presid.), Fernando Calvo González-Regueral (secret.), George Kollias (voc.)
• Programa de doctorado: Programa de Doctorado en Biociencias Moleculares por la Universidad Autónoma de Madrid
• Materias:
  • Ciencias de la vida
    • Inmunología
    • Biología molecular
  • Ciencias médicas
    • Patología
      • Oncología
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • The alternative p38 mitogen-activated protein kinases (p38MAPKs), p38γ and p38δ, regulate the response of cells to inflammatory cytokines and environmental stresses. These kinases have been implicated in the development of the immune response and in the pathogenesis of a wide range of inflammatory diseases and types of cancer. Particularly, our group has shown that p38γ and p38δ have a pro-tumorigenic role in the development of colitis-associated colon cancer (CAC), although their function seems to be dependent on the cellular context. Intestinal fibroblasts (IFs) are of key importance in the response to damage in the colon mucosa, where they regulate processes like inflammation and the proliferation of epithelial cells. Therefore, they have important functions in the development of CAC. In order to study the role of p38γ and p38δ in IFs in the development of CAC, we have generated a mouse strain (p38γ/δΔPdgfra) that does not express these kinases in intestinal subepithelial fibroblasts upon tamoxifen (TMX) administration. Using the azoxymethane/dextran sodium sulfate (AOM/DSS) model of CAC, we have found that p38γ/δΔPdgfra mice develop less and smaller tumors in the colon, and this is linked to a reduced cell proliferation and survival. Tumors from these mice also display a lower infiltration of granulocytic myeloid-derived suppressor cells (G-MDSCs) and a reduced expression of matrix metalloproteinases (MMP) 2 and 9. Using the DSS model of acute colitis, we have observed that p38γ/δΔPdgfra mice have less tissue damage, inflammation, and epithelial cell proliferation in the colon after the DSS challenge. The colon of these mice also has a reduced expression of IL11, HGF, and several MMP genes. Our in vitro experiments using IFs have revealed that p38γ/p38δ-deficient cells have a decreased inflammatory phenotype, showing an impaired expression of IL6, IL11, CSF2, and MMPs, increased myofibroblastic markers, and, presumably, a reduced tumor-promoting secretome. Finally, we have determined that p38γ and p38δ in IFs promote c-Jun transcription in an inflammatory context. Altogether, our results indicate that the alternative p38MAPKs regulate the differentiation and the paracrine function of IFs, increasing the tumorigenic role of these cells in the pathogenesis of CAC. These observations are relevant for the use of p38γ and p38δ as therapeutic targets in this disease