Glycan CA19-9 Promotes Pancreatic Disease in Mice

By Will Boggs MD

July 22, 2019

NEW YORK (Reuters Health) - The glycan carbohydrate antigen 19-9 (CA19-9), a biomarker of pancreatic inflammation and neoplasia, promotes pancreatitis and pancreatic cancer in mice, researchers report.

"We initially embarked on humanizing the mouse glycome to develop better biomarkers for early pancreatic cancer, and it was very surprising to find that sialyl-LewisA (CA19-9) promotes inflammation and cancer of the pancreas in mice," Dr. David A. Tuveson from Cold Spring Harbor Laboratory, in New York, told Reuters Health by email.

CA19-9 is found in the serum of 10% to 30% of pancreatitis patients and in 75% of pancreatic cancer patients, as well as in patients with other gastrointestinal diseases. It is also expressed in pancreatic intraepithelial neoplasms, which are precursors to pancreatic ductal adenocarcinoma (PDAC).

Dr. Tuveson and colleagues investigated the role of CA19-9 elevation in mouse and organoid models of pancreatic disease.

In a mouse model with inducible CA19-9 expression, CA19-9 elevation resulted in acute and chronic pancreatitis, they report in the June 21 issue of Science.

CA19-9 elevation was also associated with hyperactivation of epidermal growth factor receptor (EGFR) signaling.

Antibodies against CA19-9 reduced immune infiltration, ductal metaplasia and fibrosis in a preventive setting of acute pancreatitis, while reduction of CA19-9 expression resulted in partial resolution of chronic pancreatitis.

Erlotinib-induced inhibition of EGFR was not as effective as CA19-9 antibodies in mitigating pancreatitis, but caused severe weight loss in CA19-9-expressing mice.

In separate experiments, CA19-9 cooperated with the Kras(G12D) oncogene to produce aggressive pancreatic cancer in mice.

"The immediate implications are that antibodies directed against CA19-9 may be investigated in clinical trials to treat patients with pancreatitis, and perhaps even pancreatic cancer," Dr. Tuveson said. "The message for clinicians is that we may have another angle to pursue for the treatment of pancreatitis and pancreatic cancer patients."

Dr. Marco Trinchera of the University of Insubria Medical School, in Varese, Italy, who has studied CA19-9 in normal and cancer tissues of the colon and the pancreas, told Reuters Health by email, "Be very cautious with respect to this paper. There is a lot of business pressure around this antigen, widely abused as a serum tumor marker."

"This article starts from the false preconceived idea that CA19-9 is not expressed in normal tissue," he said. In contrast, "CA19-9 is largely expressed in normal tissues! This is widely published, but some people like to forget it."

The study did not have commercial funding. Dr. Tuveson and one of his co-authors are named inventors on a patent application covering the use of anti-CA19-9 antibodies for the treatment and prevention of pancreatitis.

SOURCE: https://bit.ly/2Y35JYH

Science 2019.

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