Bladder cancer cells secrete while normal bladder cells express but do not secrete AGR2

Melissa E Ho,Sara R Kim,Lawrence D True,Alvin Y Liu,Charles J Rosser,Roland Seiler,Lora Bagryanova,Lee Goodglick,Achim Fleischmann,Yuqian Gao,David Chia,Yoshiko Shimizu,Sue-Ing Quek

doi:10.18632/oncotarget.7400

Abstract

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.

Highlights

Anterior gradient 2 (AGR2) is an adenocarcinoma antigen with elevated expression in many solid tumor types including prostate, breast, pancreatic, gastrointestinal, lung
Unlike the prostate and pancreas where AGR2 is up-regulated in cancer cells compared to normal cells, AGR2 is down-regulated in a majority of bladder cancer cells compared to normal bladder cells
High serum AGR2 levels in the ng/ ml range reported in the literature were determined by a commercial enzyme-linked immunosorbent assay (ELISA) based on polyclonal antibodies of suspect specificity [21]

Summary

Introduction

Anterior gradient 2 (AGR2) is an adenocarcinoma antigen with elevated expression in many solid tumor types including prostate, breast, pancreatic, gastrointestinal, lung. AGR2 was identified as a biomarker candidate in prostate cancer by comparative transcriptomic analysis of sorted CD26+ cancer cells vs CD26+ luminal cells [7]. In this approach, genes with elevated expression encoding secreted proteins in cancer are considered to be viable candidates; genes expressed by both cancer and normal cell types are not, and are ignored. There would be very few cancerspecific biomarkers based on expression difference if examined systematically between cancer and all normal tissue This is not unexpected since every gene in the genome serves a useful function in some cell types. Whether normal AGR2-positive cells secrete or express this protein on the cell surface is not known. Both normal prostate and pancreatic epithelial cells do not express AGR2 [7, 9]

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Conclusion