Genetic Mutation Triggers Pancreatic Cancer

These characteristics are a gene that serves as a molecular on-off switch, but when mutated gets stuck on the "on" position, and is linked to a protein complex that controls activation of genes.

Scientists at The University of Texas MD Anderson Cancer Center (Houston, TX, USA) have identified the Kirsten rat sarcoma viral oncogene homolog (Kras) gene that serves as the molecular on-off switch, and an overactive protein, the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Mutated Kras trigger a chain reaction that activates the cytokine interleukin (IL-1α) expression, which in turn triggers NF-κB through a protein kinase, which blocks the inhibitor of NF-κB.

In Kras-mutated mice, microarray profiles of gene expression demonstrated that numerous NF-κB regulated inflammatory genes were present in high levels and active inhibitor of nuclear factor kappa-B kinase subunit beta (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.

Paul J. Chiao, PhD, professor in MD Anderson's Department of Molecular and Cellular Oncology and senior author of the study, explained, “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 authors concluded that the prime mover responsible for cancer-related inflammatory response and the development of pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma is the mutant Kras-initiated constitutive activation of NF-κB.

Each year in the US, 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 six months, although estimates vary. Interleukin-1α could be a new potential drug target. The study was published on January 17, 2012 in the journal Cancer Cell.

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The University of Texas MD Anderson Cancer Center