Antibodies to a CA 19-9 Related Antigen Complex Identify SOX9 Expressing Progenitor Cells In Human Foetal Pancreas and Pancreatic Adenocarcinoma

Alison M Farley,Winita Hardikar,Karl Trounson,Tatsuhiko Ikeda,Kouichi Hasegawa,Subhanwita Sakar-Dey,Kevin X Lau,David R Braxton,Bhavana Nayer,Martin F Pera,Jonathan Li

doi:10.1038/s41598-019-38988-8

Abstract

The Sialyl Lewis A antigen, or CA 19-9, is the prototype serum biomarker for adenocarcinoma of the pancreas. Despite extensive clinical study of CA 19-9 in gastrointestinal malignancies, surprisingly little is known concerning the specific cell types that express this marker during development, tissue regeneration and neoplasia. SOX9 is a transcription factor that plays a key role in these processes in foregut tissues. We report the biochemistry and tissue expression of the GCTM-5 antigen, a pancreatic cancer marker related to, but distinct from, CA19-9. This antigen, defined by two monoclonal antibodies recognising separate epitopes on a large glycoconjugate protein complex, is co-expressed with SOX9 by foregut ductal progenitors in the developing human liver and pancreas, and in pancreatic adenocarcinoma. These progenitors are distinct from cell populations identified by DCLK1, LGR5, or canonical markers of liver and pancreatic progenitor cells. Co-expression of this antigen complex and SOX9 also characterises the ductal metaplasia of submucosal glands that occurs during the development of Barrett’s oesophagus. The GCTM-5 antigen complex can be detected in the sera of patients with pancreatic adenocarcinoma. The GCTM-5 epitope shows a much more restricted pattern of expression in the normal adult pancreas relative to CA19-9. Our findings will aid in the identification, characterisation, and monitoring of ductal progenitor cells during development and progression of pancreatic adenocarcinoma in man.

Highlights

Despite extensive clinical study of the use of CA 19-9 as a serum cancer marker, and the increasing appreciation of the complexity of its biochemistry, there have been fewer investigations into the cell type specificity of expression of the CA 19-9 family of glycotopes during development, regeneration and neoplasia
The precise nature of the cells that are involved in regeneration and metaplasia of human liver, pancreas and oesophagus remains uncertain, but a better understanding the dynamics of these cell populations would inform efforts to detect and monitor disease in these organs
SOX9 is required for the development of the biliary system[45], and the pancreas[46,47,48], and for acinar to ductal metaplasia during pancreatic cancer development[19]

Summary

Introduction

Despite extensive clinical study of the use of CA 19-9 as a serum cancer marker, and the increasing appreciation of the complexity of its biochemistry, there have been fewer investigations into the cell type specificity of expression of the CA 19-9 family of glycotopes during development, regeneration and neoplasia. Ductal progenitors that proliferate in response to damage express SOX919,26, a marker of primitive embryonic precursors in both of these tissues[15,16]. More precise delineation of the key cellular intermediates in pancreatic cancer development and progression will undoubtedly lead to identification of better secreted biomarkers for early diagnosis and patient monitoring. In this context, a static picture may not be as informative as longitudinal analysis of the dynamics of expression of biomarkers for specific progenitor cell types. We demonstrated that the antigen could be detected in the sera of patients with pancreatic adenocarcinoma

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Results

Conclusion