Expression of Hypoxia-inducible Factors is Correlated with the Presence of a Fibrotic Focus and Angiogenesis in Pancreatic Ductal Adenocarcinomas

Aims: To study the expression of hypoxia-regulated markers in pancreatic ductal adenocarcinomas (PA) in relationship to the presence of a fibrotic focus, angiogenesis quantification and clinical outcome.

Methods And Results: The expression of hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, carbonic anhydrase 9 (CA9) and vascular endothelial growth factor (VEGF) was immunohistochemically detected in 50 PA and correlated with tumour characteristics, microvascular density (MVD) and survival. HIF-1alpha was expressed within tumour cells in 68%, HIF-2alpha in 46%, CA9 in 78% and VEGF in 52% of the cases. Stromal expression was also noted for HIF-2alpha and CA9 in, respectively, 42% and 48% of the cases. Tumour CA9 expression was associated with that of VEGF (P=0.004) and that of stromal HIF-2alpha (P=0.013), with the presence of a fibrotic focus (P=0.046) and with an increased MVD (P=0.034). Tumour VEGF expression correlated with the presence of a fibrotic focus (P=0.039) and a greater MVD (P=0.047). Both the presence of a fibrotic focus (P=0.0002) and high tumour CA9 expression (P=0.029) were associated with reduced overall survival.

Conclusion: The strong association of the presence of a fibrotic focus with CA9 expression and lower survival demonstrates that hypoxia-driven angiogenesis plays an important role in the progression of PA.