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 pancrea tic 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 antiapo ptotic factor to extend both normal and tumor cell survival. Recent finding s indicate that tumor cell death induced by chemotherapy and radiotherapy i s mediated by the activation of apoptosis. The fact that pancreatic cancer has an extremely malignant potential and that it is resistant to most antic ancer treatment modalities suggests that mechanisms are activated that incr ease 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. Nor mal human pancreatic tissue samples were available from 11 organ donors and 4 patients without pancreatic disease. The levels of bcl-xL mRNA expressio n were analyzed by Northern blot analysis. The exact site of bcl-xL mRNA tr anscription was determined by nonradioactive in situ hybridization. In addi tion, immunohistochemistry using specific polyclonal antibodies was used to localize the protein. Results Northern blot analysis indicated that; in comparison with the normal pancre as, bcl-xL mRNA was markedly overexpressed in 54% of the pancreatic cancer samples. Densitometric analysis revealed that pancreatic adenocarcinomas ex hibited a mean 3.4-fold increase (p < 0.01) in bcl-xL mRNA levels in compar ison with normal controls. With in situ hybridization, bcl-xL mRNA was foun d to be highly expressed in the cancer cells of tumor samples that exhibite d increased mRNA expression by Northern blot analysis. Immunohistochemical analysis revealed bcl-x immunostaining in 88% of the cancer samples. Correl ation 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 e xpression tended to live longer (median 14 months). Conclusion Enhanced expression of the antiapoptotic gene bcl-xL in pancreatic cancer a nd its association with shorter patient survival suggests hat this factor m ay 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.