Cellular Expression Patterns of Genes Upregulated in Murine and Human Colonic Neoplasms

Abstract

Markers overexpressed in colonic tumors of the multiple intestinal neoplasia (Min) mouse have been recently identified by cDNA subtractive hybridization and by microarray analysis. The significance of such a marker depends on its expression in tumor vs stromal lineages and on its expression pattern in normal tissue. From 34 differentially expressed markers, 14 were found to be expressed from supporting lineages. The markers expressed in the tumor lineage were grouped into three classes on the basis of ISH in mouse models and IHC in human adenomas. The first class includes markers expressed both in neoplastic cells and in the proliferating cells residing at the bottom of normal colonic crypts. The second class of markers shows elevated expression in neoplastic cells and also in the postmitotic Paneth cells of the small intestine. Finally, the third class of marker shows detectable intestinal expression only within tumors but not in the normal intestinal epithelium. Is such a tumor-associated marker uniquely essential for tumor growth? Deficiency for the tumor-associated glycoprotein clusterin does not affect the multiplicity or growth rate of intestinal tumors in Min mice. Thus, clusterin is a candidate secreted colon cancer marker but not a single target for chemoprevention or therapy.

IDO1+ Paneth cells promote immune escape of colorectal cancer

“…The markers Pla2g2a and Mmp7 were identified as modifiers of Min 44 and loss of Mmp7, which is essential for Paneth cell function 45 , interfered with Apc Min -induced tumor formation 46 . Moreover, expression of Paneth markers correlated with increased risk for dietary-induced sporadic intestinal cancer in mice 47 and a Paneth cell-associated gene expression pattern was identified in human intestinal tumors 48 . The presence of IDO1 + Paneth cells in intestinal cancers might provide an explanation for these observations.…”

The conserved protective cyclic AMP-phosphodiesterase function PDE4B is expressed in the adenoma and adjacent normal colonic epithelium of mammals and silenced in colorectal cancer

“…Under this interpretation, it seems paradoxical that the heterozygote, carrying one copy of the protective allele, is not significantly resistant. The sensitivity of the Pde4b +/- heterozygote implies that PDE4B must function at a level higher than the 50% level expected for the heterozygote–“haploinsufficiency.” Indeed, the Apc gene also demonstrates haploinsufficiency for intestinal adenomagenesis [ 45 ] and other processes in mice [ 46 – 48 ]. To incorporate haploinsufficiency, the canonical Tumor Suppressor Model has been amended to a “one-hit model” by Berger, Knudson and Pandolfi [ 49 ].…”