Research using mouse models reveals a novel key player in the initiation of colon cancer
Gastric and colorectal cancers account for more than 1 million deaths worldwide every year and several research groups have been working to identify the molecular events that result in the initiation and progression of these tumors. It has been established that interfering with the function of one gene, called Adenomatous Polyposis Coli (APC) has a profound effect on the cells lining the innermost layer of the colon (called the epithelium) and causes them to lose control over their proliferation leading to tumors.
Now Klaus Kaestner from the University of Pennsylvania School of Medicine has headed a study that identifies another molecular player influencing the initiation of colon cancers. This study will be published in the February 1 issue of the journal Genes and Development.
An animal model with an inactivating mutation within the mouse equivalent of the APC gene displays very similar pathology as seen in human colon cancers and develop tumor growths called polyps in their colons, eventually leading to death. Inactivating the APC gene was found, as in human cells, to cause the accumulation of a protein called beta-catenin in the nuclei of these cells.
Kaestner’s group had earlier published research on a transcription factor called Foxl1 that is also expressed in the colon, but in a different layer of cells, adjacent to the epithelium, called the mesenchyme. They had seen that mice that are deficient for the Foxl1 protein show a similar accumulation of the beta-catenin protein in the epithelium layer, yet they do not get cancers. However, combining the Foxl1 deficiency with an inactive APC gene had drastic outcomes. The group compared animals that were partially deficient for APC (containing one normal copy of the APC gene and one mutant inactive copy) in the presence or absence of Foxl1. Both animals developed tumors, however, in the absence of Foxl1, tumor frequency was more than 7-fold higher.
In addition, the animals developed tumors in the stomach. None of the tumors seen in either case were invasive leading to the conclusion that the Foxl1deficiency affects early stages in tumor formation. Additional analysis revealed that the Foxl1 deficiency affected the onset of tumor formation, accelerating them to arise in 1/3rd of the normal time. The authors examined the integrity of the APC gene in these tumor cells and found that more than ninety per cent of the tumors had lost the normal copy of the APC gene and now were completely deficient.
What is the significance of these results on understanding the initiation of colon cancer? A deficiency of Foxl1 in the mesenchymal layer of the colon leads to altered signaling to the epithelium layer and results in increased cell proliferation and turnover of this layer. In people with a genetic predisposition, like those with Familial Adenomatous Polyposis, or environmental stress that generates a spontaneous mutation in the APC gene, mutations in the Foxl1 gene or its targets may dramatically increase the likelihood that the second normal copy of the APC gene is lost or mutated, leading to the initiation of tumor formation.
This study sets a new paradigm for gastrointestinal tumorigenesis, in that genetic events outside the epithelial layer itself have a profound effect on tumor initiation. Thus it appears likely that this study will foster additional research into other mesenchymal genetic modifiers, and into potential therapeutic approaches that affect the signaling between the two cell layers.
Heather Cosel | EurekAlert!
The most recent press releases about innovation >>>
Die letzten 5 Focus-News des innovations-reports im Überblick:
Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.
As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...
Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.
Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...
For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.
While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...
An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.
The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...
A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.
Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...