Abstracts
1998 Digestive Disease Week

#1018

APOPTOSIS INHIBITION DETERIORATES THE PROGNOSIS IN PANCREATIC CANCER. H. Friess, Z. Lu1, A. Andren-Sandberg, A. Zimmermann*, G. Adler**, R. Schmid**, M.W. Büchler; Department of Visceral and Transplantation Surgery and *Institute of Pathology, University of Bern, Switzerland; **Dept of Gastroenterology, University of Ulm, Germany.

Background: Bcl-xL belongs to the bcl-2-related gene family and acts as a broad anti-apoptotic factor to extend both normal and tumor cell survival. Recent findings indicate that tumor cell death induced by chemotherapy and radiotherapy is mediated via the activation of apoptosis. The fact that pancreatic cancer has an extremely malignant potential and that it is resistant to many anticancer treatment modalities suggests that mechanisms are activated which increase the viability of pancreatic cancer cells. Therefore, in the present study we analyzed the expression of the anti-apoptotic factor bcl-xL in human pancreatic cancer and correlated the results with clinical patient parameters. Patients: Pancreatic cancer tissue samples were obtained from 32 female and 42 male patients (median age: 65 years; range: 43-79 years) undergoing surgery for pancreatic cancer. Normal pancreatic tissues were obtained from 11 previously healthy organ donors and from four patients in whom a pancreatic resection was done as an extension to another intraabdominal resection. The median age of the patients in the control group was 44 years, with a range between 24 and 71 years.

Methods: The levels of bcl-xL mRNA expression were analyzed by Northern blot analysis of total RNA. The exact site of bcl-xL mRNA transcription was determined by non-radioactive in situ hybridization. In addition, immunohistochemistry using specific polyclonal antibodies was used to localize the protein.

Results: Northem blot analysis indicated that, in comparison with the normal pancreas, bcl-xL mRNA was markedly overexpressed in 43.5% of the pancreatic cancer samples. Densitometric analysis revealed that pancreatic adenocarcinomas exhibited a mean 3.4-fold increase (p<0.002) in bcl-xL mRNA levels in comparison with normal controls. By in situ hybridization bcl-xL mRNA was found to be highly expressed in the cancer cells of tumor samples which exhibited increased mRNA expression by Northem blot analysis. Immunohistochemical analysis revealed positive bcl-x immunostaining in 88% of the cancer samples. Correlation of the molecular data with clinical patient parameters revealed that patients whose tumors exhibited low bcl-xL expression lived significantly longer after tumor resection (10.5 months) than patients whose tumors exhibited moderate bcl-xL mRNA expression (5 months) (p<0.05).

Conclusion: Enhanced expression of the anti-apoptotic gene bxl-xL in pancreatic cancer and its association with shorter patient survival suggests that this factor may enhance the viability of pancreatic cancer cells in vivo. Inhibition of apoptotic pathways might be one of the major reasons why pancreatic cancer shows only limited sensitivity to chemo- or radiotherapy.

Supported by the Sandoz Stiftung zur Förderung der Medizinischen Forschung

Copyright 1996 - 1998, SSAT, Inc. Revised 29 June 1998.