Bladder cancer cells secrete while normal bladder cells express but do not secrete AGR2
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Melissa E. Ho1,9, Sue-Ing Quek1,10, Lawrence D. True2, Roland Seiler3, Achim Fleischmann4, Lora Bagryanova5, Sara R. Kim5,6, David Chia5,6, Lee Goodglick5,6, Yoshiko Shimizu7, Charles J. Rosser7, Yuqian Gao8, Alvin Y. Liu1
1Department of Urology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA
2Department of Pathology, University of Washington, Seattle, WA, USA
3Department of Urology, University Hospital of Bern, Bern, Switzerland
4Institute of Pathology, University Hospital of Bern, Bern, Switzerland
5Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
6Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
7University of Hawaii Cancer Center, Honolulu, HI, USA
8Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
9Present address: University of California San Francisco Medical Center, San Francisco, CA, USA
10Present address: Singapore Polytechnic, Center for Biomedical & Life Sciences, Singapore
Alvin Y. Liu, e-mail: firstname.lastname@example.org
Keywords: secreted AGR2, bladder cancer, subcellular localization, urine biomarker
Received: October 15, 2015 Accepted: February 05, 2016 Published: February 15, 2016
Anterior gradient 2 (AGR2) is a cancer-associated secreted protein found predominantly in adenocarcinomas. Given its ubiquity in solid tumors, cancer-secreted AGR2 could be a useful biomarker in urine or blood for early detection. However, normal organs express and might also secrete AGR2, which would impact its utility as a cancer biomarker. Uniform AGR2 expression is found in the normal bladder urothelium. Little AGR2 is secreted by the urothelial cells as no measurable amounts could be detected in urine. The urinary proteomes of healthy people contain no listing for AGR2. Likewise, the blood proteomes of healthy people also contain no significant peptide counts for AGR2 suggesting little urothelial secretion into capillaries of the lamina propria. Expression of AGR2 is lost in urothelial carcinoma, with only 25% of primary tumors observed to retain AGR2 expression in a cohort of lymph node-positive cases. AGR2 is secreted by the urothelial carcinoma cells as urinary AGR2 was measured in the voided urine of 25% of the cases analyzed in a cohort of cancer vs. non-cancer patients. The fraction of AGR2-positive urine samples was consistent with the fraction of urothelial carcinoma that stained positive for AGR2. Since cancer cells secrete AGR2 while normal cells do not, its measurement in body fluids could be used to indicate tumor presence. Furthermore, AGR2 has also been found on the cell surface of cancer cells. Taken together, secretion and cell surface localization of AGR2 are characteristic of cancer, while expression of AGR2 by itself is not.
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