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Biology of Human Tumors

Global protease activity profiling provides differential diagnosis of pancreatic cysts

Sam L Ivry, Jeremy M Sharib, Dana A Dominguez, Nilotpal Roy, Stacy E Hatcher, Michele Yip-Schneider, C. Max Schmidt, Randall E Brand, Walter G Park, Matthias Hebrok, Grace Kim, Anthony J O'Donoghue, Kimberly S Kirkwood and Charles S. Craik
Sam L Ivry
Pharmaceutical Chemistry, University of California, San Francisco
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Jeremy M Sharib
University of California, San Francisco
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Dana A Dominguez
University of California, San Francisco
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Nilotpal Roy
Diabetes Center, University of California San Francisco
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Stacy E Hatcher
University of California, San Francisco
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Michele Yip-Schneider
Surgery, Indiana University School of Medicine
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C. Max Schmidt
Surgery, Indiana University
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Randall E Brand
Gastro., Hepatology & Nutrition, University of Pittsburgh
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Walter G Park
Medicine/Gastroenterology, Stanford University
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Matthias Hebrok
Diabetes Center, University of California, San Francisco
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Grace Kim
Pathology, Biochemistry & Biophysics
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Anthony J O'Donoghue
University of California, San Diego
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Kimberly S Kirkwood
University of California, San Francisco
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Charles S. Craik
Department of Pharmaceutical Chemistry, University of California, San Francisco
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  • For correspondence: Charles.Craik@ucsf.edu
DOI: 10.1158/1078-0432.CCR-16-2987
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Abstract

Purpose: Pancreatic cysts are estimated to be present 2-3% of the adult population. Unfortunately, current diagnostics do not accurately distinguish benign cysts from those that can progress into invasive cancer. Missregulated 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.<br /><br />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.<br /><br />Results: We determined that the activities of the aspartyl proteases gastricsin and cathepsin E are highly increased in fluid from mucinous cysts. Immunohistochemical 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.<br /><br />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.

  • Received November 28, 2016.
  • Revision received April 6, 2017.
  • Accepted April 14, 2017.
  • Copyright ©2017, American Association for Cancer Research.
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Published OnlineFirst April 19, 2017
doi: 10.1158/1078-0432.CCR-16-2987

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Global protease activity profiling provides differential diagnosis of pancreatic cysts
Sam L Ivry, Jeremy M Sharib, Dana A Dominguez, Nilotpal Roy, Stacy E Hatcher, Michele Yip-Schneider, C. Max Schmidt, Randall E Brand, Walter G Park, Matthias Hebrok, Grace Kim, Anthony J O'Donoghue, Kimberly S Kirkwood and Charles S. Craik
Clin Cancer Res April 19 2017 DOI: 10.1158/1078-0432.CCR-16-2987

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Global protease activity profiling provides differential diagnosis of pancreatic cysts
Sam L Ivry, Jeremy M Sharib, Dana A Dominguez, Nilotpal Roy, Stacy E Hatcher, Michele Yip-Schneider, C. Max Schmidt, Randall E Brand, Walter G Park, Matthias Hebrok, Grace Kim, Anthony J O'Donoghue, Kimberly S Kirkwood and Charles S. Craik
Clin Cancer Res April 19 2017 DOI: 10.1158/1078-0432.CCR-16-2987
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Clinical Cancer Research
eISSN: 1557-3265
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