Researchers from the University of Kansas have uncovered a new role for the protein adenomatous polyposis coli (APC) in suppressing colorectal cancer (CRC).
Functional loss of the APC protein is thought to be responsible for about 80% of all colon polyps, a precursor to colon cancer.
Colorectal cancer accounts for almost 50,000 deaths annually and is the second leading cause of cancer related mortality in the US.
Inflammation is seen as a major risk for CRC, with one in five persons suffering from inflammatory bowel disease developing colon cancer, a correlation associated with a poor prognosis and a high mortality rate of 50%.
The recent study entitled “Nuclear adenomatous polyposis coli suppresses colitis-associated tumorigenesis in mice” and published in the Carcinogenesis journal, reported that APC found in the cellular nucleus could protect from inflammation as well as tumor development associated with chronic colitis. Moreover, the capacity of APC to reach the nucleus affected the ability of intestinal stem cells to produce differentiated cells with specialized functions, an essential process for the renewal of the colon lining.
“It’s not widely appreciated, but there is still plenty of cell growth going on in adults, with the colon being a good example. On average, we shed and replace about 70 pounds of intestinal tissue annually, so you can imagine that this process requires exquisite control to prevent tumor formation,” Dr. Kristi Neufeld, associate professor in the Department of Molecular Biosciences, co-leader of the Cancer Biology program at the KU Cancer Center and lead author of the study, said in a University press release.
The team designed a genetic mouse model that carried a specific APC mutation, disabling its capacity to migrate into the nucleus. These mice were then induced to develop ulcerative colitis, a form of inflammatory bowel disease, and were found to carry significantly more colon tumors when compared to normal APC mice in the same inflammatory setting.
These results provided clues relative to nuclear APC prevention against inflammation and tumor development. The number of goblet cells, responsible for mucin secretion protecting the colon against microbes, was significantly decreased in APC deficient mice, correlating to the inability of this protein to reach the nucleus. This led the team to examine Muc2, one of the proteins found in the mucus, finding that its RNA levels were decreased, resulting in less mucus production and enhancing the colon’s sensitivity to organisms capable of initiating inflammation.
“Rather than being a simple, single-function protein, APC is more like a complex set of moving parts, each doing something different and most still poorly understood. Our next job is to figure out exactly how goblet cell differentiation is controlled by one or more of APC’s many components.”
The results from this study contribute to a deeper understanding of the weight inflammation has towards the biology of CRC, allowing the development of more effective, preventive, diagnostic and therapeutic regimens.
