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Clin Cancer Res. 2017 Aug 15;23(16):4865-4874. doi: 10.1158/1078-0432.CCR-16-2987. Epub 2017 Apr 19.

Global Protease Activity Profiling Provides Differential Diagnosis of Pancreatic Cysts.

Author information

1
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California.
2
Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California, San Francisco, San Francisco, California.
3
Department of Surgery, University of California, San Francisco, San Francisco, California.
4
Diabetes Center, Department of Medicine, University of California, San Francisco, San Francisco, California.
5
Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana.
6
Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
7
Department of Medicine, Stanford University School of Medicine, Stanford, California.
8
Department of Pathology, University of California, San Francisco, San Francisco, California.
9
Skaggs School of Pharmacy and Pharmaceutical Chemistry, University of California, San Diego, La Jolla, California.
10
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California. Charles.Craik@ucsf.edu.

Abstract

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.

PMID:
28424202
PMCID:
PMC5712228
DOI:
10.1158/1078-0432.CCR-16-2987
[Indexed for MEDLINE]
Free PMC Article

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