Genetic Mutation That Triggers Pancreatic Cancer Identified

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Academic Journal
Main Category: Pancreatic Cancer
Also Included In: Genetics
Article Date: 27 Jan 2012 - 10:00 PST

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Scientists at The University of Texas MD Anderson Cancer Center have identified a self-perpetuating "loop" of molecular activity that fuels pancreatic cancer by linking two signature characteristics of the disease - Kras, a gene that serves as a molecular on-off switch, but gets stuck on the "on" position when mutated, and NF-κB, a protein complex that controls activation of genes. In addition, the team identified a new potential drug target to block this process.

Overactive NF-κB fuels the disease by triggering genes that promote the growth of new blood vessels, inflammation, and block programmed cell death.

The study, funded by grants from the National Cancer Institute, including MD Anderson's Cancer Center Core Support Grant, is published in the journal Cancer Cell.

Paul Chiao, Ph.D., professor in MD Anderson's Department of Molecular and Cellular Oncology and senior author of the study, explained:

"Kras is mutated in 80 to 95 percent of pancreatic ductal adenocarcinomas, and is the most frequent mutation among all cancers."

Each year in the U.S., approximately 42,000 individuals are diagnosed with pancreatic ductal adenocarcinoma. For decades, the 5-year survival rate has been 1-3%, and median survival after diagnosis is 6 months, although estimates vary.

Interleukin-1α is a new potential drug target

Chiao explained:

"There have been many attempts to inhibit mutated Kras, but it's an elusive target that so far has defied treatment. So if we can't hit Kras, maybe we can target one of its downstream genes. This research identifies some of those genes and suggests that interleukin-1apha (IL-1α) is a potential therapeutic target."

The team identified that IL-1α plays a vital role in a self-perpetuating vicious cycle:

Mutated Kras trigger a chain reaction that activates IL-1α expression, which in turn triggers NF-κB through the protein kinase IKK2/β, which blocks the inhibitor of NF-κB. In the cell's nucleus, NF-κB controls gene transcription and regulates numerous inflammation-promoting genes, including IL-1α. Together with a protein called p62, IL-1α triggers NF-κB, that in turn cycles back to perpetuate the loop by triggering its activators.

Chiao, who has three grants from the National Cancer Institute to research pancreatic cancer, said:

"It's a vicious cycle. We study signaling transduction pathways to try to find out why it's such a bad disease and to find a weak point for targeted therapy."

The researchers conclude:

"Our findings suggest that the prime mover responsible for cancer-related inflammatory response and the development of pancreatic intraepithelial neoplasia (precancerous lesions) and pancreatic ductal adenocarcinoma is the mutant Kras-initiated constitutive activation of NF-κB.

This process produces a pro-tumor microenvironment by promoting generation of new blood vessels, inflammation, and tissue repair comparable to conditions found in inherited pancreatitis, inflammation of the pancreas that is associated to the development of cancer."

Kras mutation, IL-1α, NF-κB are correlated and associated with poor survival

In a series of experiments, the team examined mouse and human tumors, and mouse strains with mutated Kras expression in their pancreases and found:

• In order for the Kras-mutated mice to develop precancerous legions or pancreatic cancer, Active IKK2/β - the activator of NF-κB - was required.
• Deletion of IKK2/Beta interrupted Kras-stimulated inflammation and cell proliferation, indicating that chronic inflammation plays a vital role in promoting pancreatic cancer development.
• In Kras-muated mice, microarray profiles of gene expression demonstrated that numerous NF-κB regulated inflammatory genes were present in high levels and active IKK2/β but only found at lower levels in mice with IKK2/β knocked out.
• Just like the Kras-mutated mice, they found high expression of the same inflammatory genes in human pancreatic tumors. High expression of these genes was linked to positive lymph node status, late tumor stage, high-risk and poor survival.
• Expression of several genes controlled by NF-κB progressed from low levels in normal pancreases to higher levels in precancerous lesions and tumors, including IL-α.
• Although IL-1α was known to be both a target of and an inducer of NF-κB, its expression had never been associated to mutated Kras. The researchers discovered that downstream targets of Kras, including IL-1α, are interrupted when IKK2/β is inactivated.
• Overexpression of IL-1α, Kras mutation, and NF-κB were found to be correlated and linked to poor survival.
• IL-1a and p62 sustain the continued activation of NF-κB and its gene transcription activity.

Co-authors with Chiao are Jianhua Ling, Ph.D., Rulying Zhao, M.D., Ph.D., Qianghua Xia, Ph.D., Zhe Chang, Ph.D., and Mien-Chie Hung, Ph.D., of MD Anderson's Department of Molecular and Cellular Oncology; Ya'an Kang, M.D., Ph.D., and Jason Fleming, M.D., of MD Anderson's Department of Surgical Oncology; Huamin Wang, M.D., Ph.D., and Jinsong Liu, M.D., Ph.D., of MD Anderson's Department of Pathology; Dung-Fang Lee, Ph.D., and Ihor Lemischka, Ph.D., of the Black Family Stem Cell Institute of Mount Sinai School of Medicine; Jin Li, Ph.D., of the Center for Applied Genomics of the Children's Hospital of Philadelphia; and Bailu Peng, Ph.D. of the Guangdong Entomological Institute, Guangdong, China.

Written by Grace Rattue
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today

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