Heterozygous Fbxw7 propellor tip (R482Q) mutations promote intestinal tumorigenesis on an Apc mutant background.
The first signal consists in the presentation of an antigen to TCR by a major histocompatibility complex molecule on an APC.
On an Apc mutant background, heterozygous null Fbxw7 mutations promote tumour growth, but have a much weaker effect than heterozygous propellor tip mutants.
On an Apc mutant background, polyposis developed more rapidly in R482Q than Fbxw7 +/− animals, and there was additionally a relative shift in polyp numbers to SB1, a feature previously associated with more severe disease.
We therefore compared polyp formation in R482Q/+ and Fbxw7 +/− mice on an Apc mutant (Min or 1322T) background using age of developing symptoms as a measure of disease severity.
If the number of sites on an APC that can form stable interactions with CD8+ T cells are limiting, perhaps CD8+ T cells compete for progression to phase two.
Contrary to the 'just enough' model, however, the murine Fbxw7 +/− genotype did promote intestinal tumorigenesis, whether alone or on an Apc mutant background, whereas we predict that this genotype causes insufficient functional derangement to promote human tumorigenesis.
Once a T cell encounters its specific antigen on an APC in the lymph nodes or spleen in an appropriate MHC context, it rapidly reorients its cellular organelles to the contact area in a process accompanied by complex structural and cytoskeletal changes.
In contrast, APCMinPPAR β null mouse showed no requirement for PPAR β for polyp formation (Barak et al, 2002), indicating that the increased activity of PPAR β on an APC-null background might be one of the factors supporting colorectal tumorigenesis (Michalik et al, 2004).
Squamous cell carcinoma decreased over the same period by -0.0881 cases per 100,000 per year on average, give an APC of -3.74%.
