The role of hypoxia and its interaction with the PI3K/Akt pathway in the pathogenesis of malignant pleural mesothelioma

Carbonic Anhydrase (CA) IX, a surrogate marker of hypoxia, is upregulated downstream of the stabilisation of hypoxia-inducible factor (HIF)-1alpha and is over-expressed in solid tumours. Protein Kinase B, or Akt, known to have important intracellular roles including resistance to apoptosis, is activated in human malignancies and upregulated in hypoxic conditions.;This body of work examined the expression of CA IX and phosphorylated Akt (pAkt) in tumour samples from patients with MPM, correlating expression with established prognostic factors. The role of pAkt and HIF-1alpha in the survival of an MPM cell line exposed to hypoxic conditions was also examined. Tumour samples from 200 patients with MPM were stained using pAkt and CA IX specific antibodies. The effect of hypoxia on apoptosis was evaluated in 4 mesothelioma cell lines and 1 benign mesothelial cell line, in the presence or absence of the phosphatidylinositol-3-kinase inhibitor, LY294002.;There was a positive association between the level of CA IX and pAkt staining, implying that intra-tumoural hypoxia may be a stimulus for Akt phosphorylation. On multivariate analysis increased expression of nuclear pAkt was found to be associated with a poor survival. In-vitro cell culture work showed that, although pAkt is expressed in normoxic conditions in the cell lines studied, in the JU77 cell line the rates of apoptosis were significantly increased in hypoxic conditions when the phosphorylation of Akt was blocked by LY294002.;This work provides evidence for the anti-apoptotic role of pAkt in hypoxic conditions in solid human malignancies. Phospho-Akt may represent a novel therapeutic target in MPM.