Validación de las quinasas de estrés p38MAPKs como nuevos biomarcadores tumorales. Análisis de su papel en cáncer de colon asociado a colitis

Resumen

Colon cancer is the third leading cause of tumour-provoked deaths. The risk of developing colon cancer is significantly increased in patients suffering chronic inflammatory bowel diseases, such as Crohn’s diseases or Ulcerative colitis, along the years. Our laboratory is studying the role of p38γ and p38δ in the development of colon cancer associated to colitis (CAC). We have described that the incidence of CAC is decreased in p38γ and p38δ-deficent mice. We have also been described that p38γ and p38δ have both pro-tumorigenic and anti-tumorigenic roles in tumour development and progression; this suggest that p38γ and p38δ could play different biological function depending on the cellular context. We decided to study the role of p38γ and p38δ in two different compartments that are important for colon cancer associated to colitis, by using two different conditional knockout mice: The VillinCre-p38γ/δ-/- (which have a deletion of p38γ and p38δ in the intestinal epithelial cells) and the LysCre-p38γ/δ-/- (which have a deletion of p38γ and p38δ in the myeloid cells). We found that deletion of p38γ and p38δ in the intestinal epithelial cells increases tumour formation, with a parallel increase in inflammatory cytokine production and recruitment of monocyte myeloid derived suppressor cells; while the deletion of p38γ and p38δ in the myeloid cells decreases tumour formation, and increases tumour cell apoptosis and CD4+ T cells in tumours. We also found that deletion of p38γ and p38δ in the intestinal epithelial cells enhance the severity of acute colitis pathology, with increased epithelial damage, inflammatory cytokine induction, and IGFBP-3 and osteopontin production. On the other hand, deletion p38γ and p38δ in the myeloid cells protects the intestinal epithelium against colitis-induced damage. Analysis of immune cell populations in LysCre-p38γ/δ-/- mice showed an increase in macrophages, neutrophils and CD4+ T cells in colon during colitis. Together, our results show that p38γ and p38δ play different roles in the development of colitis or colitis associated cancer, depending on the cellular type.