Toll-like receptors 2, 4 and 9 and hypoxia markers HIF-1alpha and CAIX in pancreatic intraepithelial neoplasia.

Pancreatic cancer arises from precursor lesions called pancreatic intraepithelial neoplasia (PanIN) characterized by inflammatory microenvironment. In pancreatic cancer, strong innate immunity and hypoxia responses are typical. Occurrence and relationship of these responses in human PanINs is unknown. We have studied the expression of toll-like receptors (TLR) TLR2, TLR4 and TLR9, and hypoxia markers HIF-1alpha and Carbonic anhydrase IX (CAIX) in normal and inflamed pancreatic ducts, in PanINs and in cancers. The samples of 69 surgically resected pancreatic ductal adenocarcinoma patients were stained using immunohistochemistry. We found TLR2, TLR9, HIF-1alpha and CAIX to be prominently expressed in pancreatic intraepithelial neoplasia. Expression of TLR2 showed a linear increase from PanIN1 to PanIN3, while the highest TLR4 expression was detected in inflamed ducts, and TLR9 expression in PanIN1 lesions. Within the PanIN1-group, nuclear HIF-1alpha correlated with membranous and cytoplasmic TLR2 expression (ρ = 0.982 and 0.815; p < 0.001 and p = 0.025, respectively), and in the PanIN2-group nuclear HIF-1alpha correlated with nuclear TLR9 expression 0.636, p = 0.026). Our findings show that the expression of TLRs 2, 4 and 9, and hypoxia markers HIF-1alpha and CAIX is abnormal in pancreatic intraepithelial neoplasia suggesting that both the innate immunity activation and hypoxia response are involved in early pancreatic carcinogenesis. However, these processes might be independent.