gms | German Medical Science

Introduction: Pancreatic cancer is a devastating disease because of late diagnosis, lack of effective therapeutics and very poor prognosis. Pancreatic Intraepithelial Neoplasias (PanINs) and benign Intraductal Papillary Mucinous Neoplasias (IPMNs) are precursor lesions which could be an ideal target for chemoprevention. Obesity and high fat intake are risk factors for the development of pancreatic cancer. Arachidonic acid metabolizing enzymes as cyclooxygenases (COX) and lipoxygenases (LOX) play a key role, e.g. overexpression of COX-2 in transgenic mice promotes the development of pancreatic cancer. Furthermore, 5-LOX is pro-tumorigenic and overexpressed in pancreatic adenocarcinoma. Whether the 5-LOX pathway is activated in PanIN lesions or IPMNs was investigated in this study.

Materials and Methods: 5-LOX was immunostained in tissues from patients with pancreatic adenocarcinomas (PC; n=14) or chronic pancreatitis (CP; n=16), normal pancreatic tissues from multi-organ donors (NP; n=10), carcinogen (BOP)-treated hamsters (n=3), EL-Kras transgenic mice (n=9) and P48CreKras transgenic mice (n=6) as well as normal hamster (n=3) and mouse pancreatic tissues (n=6). In addition, 5-LOX mRNA expression was quantitatively analyzed in human tissues from PC (n=29), CP (n=16) and benign and malignant IPMNs (n=39) in comparison to NP (n=22) by real-time RT-PCR.

Results: Intense 5-LOX staining was evident in cancer cells and all grades of PanINs of 13/14 human pancreatic adenocarcinoma and 13/16 CP tissues while only a small proportion of ductal cells (<10%) in NP tissues were stained. However, incidentally found PanIN-1a lesions stained positive. Similarly, PanINs in BOP-treated hamsters, EL-Kras and P48CreKras mice showed positive staining, whereas normal ductal cells were completely negative. 5-LOX staining was significantly different between normal and pathologic pancreatic tissues (P<0,01). 5-LOX mRNA was also significantly up-regulated in PC and CP tissues as well as malignant IPMNs compared to NP tissues or benign IPMNs (P<0,001).

Conclusion: This study demonstrates that pro-tumorigenic 5-LOX is up-regulated in human PanINs, malignant IPMNs and cancer cells as well as early lesions of pancreatic cancer in three different animal models. These findings provide convincing evidence that 5-LOX plays a key role in pancreatic carcinogenesis and serves as a new tumor promoter. This enzyme is an attractive target for the prevention and therapy of pancreatic cancer, since 5-LOX inhibitors can be administered orally and are well tolerated.