An immunohistochemical assessment of cathepsin D in gastric carcinoma: its impact on clinical prognosis.
BACKGROUND
In the context of tumor-associated proteolysis, the prognostic value of cathepsin D in breast carcinoma has been studied but its role is controversial in relation to gastrointestinal carcinoma. The aim of the current study was to determine whether cathepsin D is a prognostic parameter for gastric carcinoma, and also to consider interaction with the urokinase-plasminogen activator (uPA) system as an established risk factor for tumor-associated proteolysis.


METHODS
In a consecutive prospective series of 203 gastric carcinoma patients, expression of cathepsin D in tumor cells was semiquantitatively analyzed with immunohistochemistry (scored 0-3). Median follow-up time was 31 months (range, 9-56 months). Kaplan-Meier (log rank) and multivariate Cox analyses were used to analyze survival.


RESULTS
Kaplan-Meier analysis (log rank statistics) revealed significant association of increasing cathepsin D detection with poorer disease free survival (P = 0.0042) and poorer overall survival (P = 0.0018) of curatively resected patients. Overall survival of all patients was not significantly correlated. Multivariate analysis of established risk factors for gastric carcinoma, including the uPA system, identified cathepsin D as a new and independent prognostic parameter for disease free survival (P = 0.020; relative risk, 2.98; 95% confidence interval, 1.28-6.91). Plasminogen activator inhibitor type-1 as a representative of the uPA system was confirmed as a strong independent factor for disease free and overall survival. Chi-square analysis showed significant correlation of higher cathepsin D levels with Laurén's diffuse-type carcinomas and strong evidence of uPA receptor in tumor cells. However, a subgroup analysis performed according to Laurén's classification revealed a univariate prognostic impact of cathepsin D on both diffuse and intestinal types without independent value. For patients with high levels of uPA receptor (scores of 2 and 3, n = 132), a highly significant association of increasing evidence of cathepsin D with disease free survival (P < 0.0001) and overall survival (P < 0.0001) was observed for curatively resected patients. Significant association with survival was also observed for all patients (P = 0.0407).


CONCLUSIONS
Cathepsin D is a new functional prognostic parameter for gastric carcinoma patients with independent value for disease free survival. Moreover, this study indicates that consideration of more than one tumor-associated protease could lead to a more individualized estimation of risk for carcinoma patients.
Allgayer
H
H
Department of Surgery, Klinikum Grosshadern, Ludwig Maximilians University of Munich, Germany.
Babic
R
R
Grützner
K U
KU
Beyer
B C
BC
Tarabichi
A
A
Wilhelm Schildberg
F
F
Heiss
M M
MM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D002402:Cathepsin D / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010960:Plasminogen Activators / Q000378:metabolism; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012307:Risk Factors; D015842:Serine Proteinase Inhibitors / Q000378:metabolism; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D016019:Survival Analysis; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D015415:Biomarkers; D015842:Serine Proteinase Inhibitors; D010960:Plasminogen Activators; D014568:Urokinase-Type Plasminogen Activator; D002402:Cathepsin D