Moderate activation of the apoptosis inhibitor bcl-xL worsens the prognosis in pancreatic cancer

Objective: To analyze the expression of the antiapoptotic gene bcl-xL in human pancreatic cancer and to correlate the results with clinical patient parameters. Summary Background Data: Bcl-xL belongs to the bcl-2-related gene family and acts as a broad antiapoptotic factor to extend both normal and tumor cell survival. Recent findings indicate that tumor cell death induced by chemotherapy and radiotherapy is mediated by the activation of apoptosis. The fact that pancreatic cancer has an extremely malignant potential and that it is resistant to most anticancer treatment modalities suggests that mechanisms are activated that increase the viability of pancreatic cancer cells. Methods: Seventy-four pancreatic cancer tissue samples were obtained from 32 female and 42 male patients undergoing surgery for exocrine pancreatic cancer. Normal human pancreatic tissue samples were available from 11 organ donors and 4 patients without pancreatic disease. The levels of bcl- xL mRNA expression were analyzed by Northern blot analysis. The exact site of bcl-xL mRNA transcription was determined by nonradioactive in situ hybridization. In addition, immunohistochemistry using specific polyclonal antibodies was used to localize the protein. Results: Northern blot analysis indicated that, in comparison with the normal pancreas, bcl-xL mRNA was markedly overexpressed in 54% of the pancreatic cancer samples. Densitometric analysis revealed that pancreatic adenocarcinomas exhibited a mean 3.4-fold increase (p < 0.01) in bcl-xL mRNA levels in comparison with normal controls. With in situ hybridization, bcl-xL mRNA was found to be highly expressed in the cancer cells of tumor samples that exhibited increased mRNA expression by Northern blot analysis. Immunohistochemical analysis revealed bcl-x immunostaining in 88% of the cancer samples. Correlation of the molecular data with clinical patient parameters revealed that patients whose tumors exhibited no, faint, or weak bcl-xL expression lived significantly longer after tumor resection (median 12 months) than patients whose tumors exhibited moderate bcl-xL mRNA expression (median 5 months) (p < 0.05). However, 5 patients whose tumors exhibited intense bcl-xL mRNA expression tended to live longer (median 14 months). Conclusion: Enhanced expression of the antiapoptotic gene bcl-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 reasons why pancreatic cancer shows only limited sensitivity to anticancer treatment.