Expression of pancreatitis-associated protein (PAP) in human pancreatic cancer: analyis in serum, pancreatic juice and tissues
Department of Internal Medicine and Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
AIM: PAP is almost absent in the normal pancreas, but is strongly induced in acinar cells during acute pancreatitis. On the other hand, we have reported an ectopic expression of PAP in various human cancers including pancreatic ductal adenocarcinoma. However, the mechanism and significance of cancerous expression of PAP are still unknown. We aimed to elucidate the clinical significance of PAP expression in pancreatic cancer. METHODS: Sera were collected from 71 patients with pancreatic cancer (PC) and pancreatic juice was obtained by endoscopic aspiration via the duodenal papilla from 22 patients with PC. PAP concentrations were determined using PancrePAP ELISA kit (Dynabio, Marseille, France) after 1:100 dilution. The tissue expression of PAP was analyzed with immunohistochemstry using formalin-fixed, paraffin-embedded sections from 38 patients with PC. RESULTS: Serum PAP was positive (> 55 ng/ml) in 40.8% (29/71), which was significantly higher than the positive rate (9.4%, 3/32) in chronic pancreatitis (CP). Serum PAP levels in cases of tumor size larger than 6 cm were significantly higher than those in cases of tumors smaller than 6 cm. Elevated serum PAP levels in 2 cases were normalized after the curative resection of tumor. There was no significant relationship between the serum PAP levels and the location of pancreatic cancer. When the cut-off value was set at 350 ng/ml, which was the mean+3SD of the PAP levels in the control group (silent gallstones, pancreatic cyst, etc), PAP in pancreatic juice (PJ-PAP) was positive in 54.5% (12/22) of PC patients, whereas the positive rate in CP patients was 24.5% (12/49). There was no significant correlation between serum PAP and PJ-PAP, and combination assay of serum PAP and/or PJ-PAP detected 80% (12/15) of PC case. PJ-PAP showed no significant relationship with the tumor size of PC. There were no significant relationships between PJ-PAP and K-ras (P=0.581) or p53 (P=0.278) mutations. At a tissue level, PAP was not expressed in the normal pancreas, but was expressed in 78.9% (30/38) of PC. PAP was localized in the cytoplasm of cancer cells, and was also expressed in acinar cells of obstructive pancreatitis regions. The expression of PAP was significantly correlated with nodal involvement, liver metastasis, and survival, and multivariate analysis showed that PAP was a significant prognostic factor in PC patients. CONCLUSIONS: PAP was expressed in pancreatic cancer cells as well as in acinar cells of obstructive pancreatitis, was secreted into pancreatic juice and was detected in sera of patients with pancreatic cancer. These results suggest that serum PAP determination contributes to the detection of pancreatic cancer and that PAP is an indicator of malignant grade of cancer cells.
Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in poster session 797 (Manifestations of cancer).