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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 - coselpie@cshl.edu
Cold Spring Harbor Laboratory
De cercetare, folosind modele de mouse-ului, aratã un roman actor-cheie în iniþierea cancerului de colon - Research using mouse models reveals a novel key player in the initiation of colon cancer - articole medicale engleza - startsanatate