Abstracts
1997 Digestive Disease Week

Apoptosis is switched off in pancreatic cancer.

H Friess, HU Graber, A Zimmermann, M Korc, G Adler, R Schmid, MW Buchler. Departments of Visceral and Transplantation Surgery and Pathology, University of Bern, Switzerland; Department of Gastroenterology, University of Ulm, Germany; Department of Medicine, University of California Irvine.

Apoptosis--also called programmed cell death--plays an important role in tissue homeostasis and in the elimination of abnormal cells, thereby preventing malignant cell transformation. Bak is an apoptosis promoting gene which belongs to the Bcl-2 gene family. Pancreatic cancer is a rapid growing malignancy with poor prognosis. The reasons for its aggressive growth behavior are not known. In the present study we analyzed the expression of Bak in human pancreatic cancer to evaluate if apoptosis is activated or inhibited in this malignancy.

Patients: Pancreatic cancer tissues were obtained from 18 male and 8 female patients (median age: 67 years; range: 32-78 years) undergoing resection for pancreatic cancer (3 stage I, 12 stage II, 11 stage III). Normal pancreatic tissue samples were obtained from 12 previously healthy organ donors through an organ donor program (9 male, 3 female; median age: 26 years; range: 10-62 years).

Methods: Bak mRNA expression was analyzed by Northern blot analysis. The exact site of Bak mRNA localization was determined by in sltu hybridization. The results of the Northern blots were quantified by laser densitometry for statistical analysis. The in situ hybridization slides were examined by two independent pathologists.

Results: Bak mRNA expression was 2.5-fold increased in the pancreatic cancer samples in comparison with normal pancreas (p<0.001). Elevated levels were found in 58% (15/26) of pancreatic cancer tissues. If only samples with increased Bak expression were used for statistical analysis the increase was 4.3-fold compared to normal controls (p<0.001). There was no correlation between tumor-stage, patient survival and Bak expression. By in situ hybridization, low to moderate levels of Bak mRNA expression were present in ductal and islet cells in the normal pancreas. In the cancer tissues we also found only low levels of Bak mRNA in the cancer cells themselves. In contrast, in regions with chronic pancreatitis-like lesions surrounding the tumor mass there was consistently high Bak mRNA expression in acinar and in inflammatory cells.

Conclusion: Downregulation of Bak in pancreatic cancer cells, but not in the cells within the regions of perifocal chronic pancreatitis, suggests that apoptosis is not activated in pancreatic cancer. The absence of apoptosis promoting gene products in pancreatic cancer might contribute to the aggressive growth behavior and spread of this tumor.