Global Protease Activity Profiling Provides Differential Diagnosis of Pancreatic Cysts.

Journal Article (Journal Article)

Purpose: Pancreatic cysts are estimated to be present in 2%-3% of the adult population. Unfortunately, current diagnostics do not accurately distinguish benign cysts from those that can progress into invasive cancer. Misregulated pericellular proteolysis is a hallmark of malignancy, and therefore, we used a global approach to discover protease activities that differentiate benign nonmucinous cysts from premalignant mucinous cysts.Experimental Design: We employed an unbiased and global protease profiling approach to discover protease activities in 23 cyst fluid samples. The distinguishing activities of select proteases was confirmed in 110 samples using specific fluorogenic substrates and required less than 5 μL of cyst fluid.Results: We determined that the activities of the aspartyl proteases gastricsin and cathepsin E are highly increased in fluid from mucinous cysts. IHC analysis revealed that gastricsin expression was associated with regions of low-grade dysplasia, whereas cathepsin E expression was independent of dysplasia grade. Gastricsin activity differentiated mucinous from nonmucinous cysts with a specificity of 100% and a sensitivity of 93%, whereas cathepsin E activity was 92% specific and 70% sensitive. Gastricsin significantly outperformed the most widely used molecular biomarker, carcinoembryonic antigen (CEA), which demonstrated 94% specificity and 65% sensitivity. Combined analysis of gastricsin and CEA resulted in a near perfect classifier with 100% specificity and 98% sensitivity.Conclusions: Quantitation of gastricsin and cathepsin E activities accurately distinguished mucinous from nonmucinous pancreatic cysts and has the potential to replace current diagnostics for analysis of these highly prevalent lesions. Clin Cancer Res; 23(16); 4865-74. ©2017 AACR .

Full Text

Duke Authors

Cited Authors

  • Ivry, SL; Sharib, JM; Dominguez, DA; Roy, N; Hatcher, SE; Yip-Schneider, MT; Schmidt, CM; Brand, RE; Park, WG; Hebrok, M; Kim, GE; O'Donoghue, AJ; Kirkwood, KS; Craik, CS

Published Date

  • August 2017

Published In

Volume / Issue

  • 23 / 16

Start / End Page

  • 4865 - 4874

PubMed ID

  • 28424202

Pubmed Central ID

  • PMC5712228

Electronic International Standard Serial Number (EISSN)

  • 1557-3265

International Standard Serial Number (ISSN)

  • 1078-0432

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.ccr-16-2987

Language

  • eng