Hypoxic markers in non-small cell lung cancer
thesisposted on 2014-12-15, 10:30 authored by Daniel Swinson
Hypoxia is an important factor in the pathogenesis of solid tumours. Hypoxia inducible factors (HIF)-1alpha and HIF-2alpha are transcription factors that in part mediate the cellular response to hypoxia. These transcription factors are involved in the regulation of angiogenesis, anaerobic metabolism, pH homeostasis, erythropoiesis and cell death.;Immunohistochemical (IHC) assays were optimised for HIF-1alpha and one of its transcriptional targets, Carbonic Anhydrase (CA) IX. Attempts to optimise an IHC assay for HIF-2alpha failed to produce reproducible staining. A scoring system was also devised to assess the extent of tumour necrosis (TN) in tumour sections. The expression of these factors was assessed in a retrospective series of patients who had NSCLC tumours resected with curative intent. The expression of EGFR, p53, Bcl-2, MMP-2 and MMP-9 and angiogenesis had previously been assessed.;Extensive TN, perinuclear (p) CA IX and high HIF-1alpha expression were associated with a poor prognosis. PCA IX, stage, gender, MMP-9 and angiogenesis were independent prognostic factors.;The spatial relationship between membranous CA IX expression and TN and tumour microvessels support other studies proposing that CA IX is a marker of tumour hypoxia.;EGFR expression was associated with pCA IX, membranous (m)CA IX and HIF-1alpha expression. In vitro studies demonstrated that prolonged treatment with the EGFR tyrosine kinase inhibitor, ZD 1839 suppressed CA IX expression. These results suggest that activated EGFR may induce CA IX. As such co-expression of these factors may identify patients that are more likely to respond to EGFR targeted therapies.