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Molecular master switch for pancreatic cancer identified, potential predictor of treatment outcome
By Dross at 2013-02-13 23:38
Molecular master switch for pancreatic cancer identified, potential predictor of treatment outcome

PHILADELPHIA – A recently described master regulator protein may explain the development of aberrant cell growth in the pancreas spurred by inflammation

A team from the Perelman School of Medicine at the University of Pennsylvania profiled gene expression of mouse pancreatic ductal and duct-like cells from different states - embryonic development, acute pancreatitis and K-ras mutation-driven carcinogenesis - to find the molecular regulation of these processes.

Broadly speaking, two cellular compartments are important in a normal pancreas, endocrine cells, which produce hormones including insulin, and exocrine cells – acinar and ductal -- which make and secrete digestive enzymes.

A cover article from the lab of Anil Rustgi, MD, Chief, Division of Gastroenterology, published early online in Genes and Development, details the molecular changes of exocrine cells during inflammation, so-called acinar-ductal metaplasia (ADM), a prelude to pancreatic ductal adenocarcinoma.

They used cell lineage tracing to follow what happens to the regulator protein called Prrx1 as cells change characteristics. Another protein, Sox9, which is downstream of Prrx1 in the cell signal pathway, is also important in understanding how pancreatic cancer forms, as the group has established the first link of Prrx1 to Sox9. The findings suggest that Prrx1 and Sox9 influence the emergence of an intermediate cell type that can give rise to cancer.

Inflammation is Key Culprit

Inflammation of the pancreas, or pancreatitis, is a leading reason for hospital admission, according to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and chronic pancreatitis is a risk factor for cancer of the pancreas. Each year, about 210,000 people in the United States are admitted to the hospital with acute pancreatitis.

Acute pancreatitis is caused by alcohol abuse, gallstones, and autoimmune disorders. When things go wrong, inflammatory pancreatitis happens, and the change from an acute state to a chronic state can lead to cancer.

When a patient recovers from pancreatitis, the change in cell fate reverts to the original cell type. But, if the pancreatitis is chronic, changed cells stay changed.

"We hope that studies like this one that identify key molecules and pathways that govern the cancerous fate of cells can be used as diagnostic predictors of treatment outcome and severity for cancer," says Rustgi.



3 comments | 2287 reads

by gdpawel on Thu, 2013-02-14 00:54
It is likely that the protein is also highly significant for other inflammatory diseases.

The research results have been published in the American journal Gastroenterology.

Excessive alcohol intake and gall stones are known risk factors for acute pancreatitis. However, as yet no explanation has been found for what actually happens in the body in cases of acute pancreatitis.

Current research shows that calcium-sensitive proteins found in the body, for example calcineurin, promote inflammation, but it is not known exactly how.

Henrik Thorlacius and Maria Gomez at the University's Department of Clinical Sciences in Malmö have investigated this in more detail. The focus is on a family of proteins linked to calcineurin, called NFAT, the role of which in acute pancreatitis has not previously been studied.

"The protein has an unexpectedly major role in the development of inflammation in the pancreas. Now there is a clear target for the development of drugs and treatments", says Henrik Thorlacius, Professor of Surgery at Lund University and a doctor at Skåne University Hospital.

In experiments on mice, the researchers found a number of links between NFAT and acute pancreatitis. NFAT, and especially the variant NFATc3, were found to regulate the activity of trypsinogen (a precursor form of the digestive enzyme trypsin), which can affect the risk of acute pancreatitis. The activation of NFATc3 was also found to encourage inflammation and tissue damage in the pancreas in various other ways.

"In our study, we saw that the aorta, spleen and lungs were also affected. The results therefore suggest that the NFAT protein plays a part in the development of inflammatory diseases on a more general level", says Henrik Thorlacius.

The findings open up new opportunities for research on treatment and drugs, both for acute pancreatitis and for other acute inflammatory diseases, such as blood poisoning and inflammatory bowel disease.

"An effective drug needs to contain a substance that stops the activation of NFATc3 without producing serious side-effects", says Professor Thorlacius.

The NFAT proteins function as transcription factors, which means that they can be bound to the body's DNA and regulate the expression of specific genes in different cells. They have so far primarily been associated with immune cells.

References: Article title: 'NFATc3 Regulates Trypsinogen Activation, Neutrophil Recruitment, and Tissue Damage in Acute Pancreatitis in Mice' Published in: Gastroenterology

Citation: Lund University. "Inflammatory Diseases, Pancreatitis Likely Caused By Immune System Protein." Medical News Today. MediLexicon, Intl., 4 Sep. 2012

by gdpawel on Sun, 2013-02-17 08:12
A recently described master regulator protein may explain the development of aberrant cell growth in the pancreas spurred by inflammation

A team from the Perelman School of Medicine at the University of Pennsylvania profiled gene expression of mouse pancreatic ductal and duct-like cells from different states - embryonic development, acute pancreatitis and K-ras mutation-driven carcinogenesis - to find the molecular regulation of these processes.

Broadly speaking, two cellular compartments are important in a normal pancreas, endocrine cells, which produce hormones including insulin, and exocrine cells - acinar and ductal - which make and secrete digestive enzymes.

A cover article from the lab of Anil Rustgi, MD, Chief, Division of Gastroenterology, published early online in Genes and Development, details the molecular changes of exocrine cells during inflammation, so-called acinar-ductal metaplasia (ADM), a prelude to pancreatic ductal adenocarcinoma.

They used cell lineage tracing to follow what happens to the regulator protein called Prrx1 as cells change characteristics. Another protein, Sox9, which is downstream of Prrx1 in the cell signal pathway, is also important in understanding how pancreatic cancer forms, as the group has established the first link of Prrx1 to Sox9. The findings suggest that Prrx1 and Sox9 influence the emergence of an intermediate cell type that can give rise to cancer.

Inflammation is Key Culprit

Inflammation of the pancreas, or pancreatitis, is a leading reason for hospital admission, according to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and chronic pancreatitis is a risk factor for cancer of the pancreas. Each year, about 210,000 people in the United States are admitted to the hospital with acute pancreatitis.

Acute pancreatitis is caused by alcohol abuse, gallstones, and autoimmune disorders. When things go wrong, inflammatory pancreatitis happens, and the change from an acute state to a chronic state can lead to cancer.

When a patient recovers from pancreatitis, the change in cell fate reverts to the original cell type. But, if the pancreatitis is chronic, changed cells stay changed.

"We hope that studies like this one that identify key molecules and pathways that govern the cancerous fate of cells can be used as diagnostic predictors of treatment outcome and severity for cancer," says Rustgi.

References:

Co-authors include first author Maximilian Reichert, Shigetsugu Takano, Johannes von Burstin, Kaori Ihida-Stansbury, Christopher Hahn, Steffen Heeg, Andrew D. Rhim, and Ben Z. Stanger, all from Penn

The work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (DK060694, P30-DK050306, DK088945, DK007066, CA117969, DK083355, DK083111), the National Pancreas Foundation , the Honjo International Scholarship Foundation , the Deutsche Krebshilfe, the American Society Grant (RP-10-033-01-CCE).

Citation: University of Pennsylvania School of Medicine. "Identification Of Molecular Master Switch For Pancreatic Cancer, Potential Predictor Of Treatment Outcome." Medical News Today. MediLexicon, Intl., 15 Feb. 2013

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