Sci. STKE, 8 February 2005
CANCER BIOLOGY Trans-Cellular Genetic Modification in Cancer
Gastric and colon cancers contribute to more than 1 million deaths per year worldwide. Many tumors harbor mutations in a gene called adenomatous polyposis coli (APC) that affect proliferation of gastrointestinal epithelial cells. Inactivation of APC results in nuclear accumulation of β-catenin, a downstream effector of the Wnt signaling pathway that controls cell proliferation. Mice with an inactivating mutation in multiple intestinal neoplasia (Min), the ortholog of APC, also exhibit intestinal tumors and up-regulated Wnt signaling. Perreault et al. found that if mice partially deficient for Min (harboring one inactive Min gene copy) were crossed with mice deficient in a transcription factor called Foxl1, intestinal tumor frequency increased sevenfold and additional tumors developed in the stomach. Additional loss of Foxl1 did not change the rate of apoptosis in epithelial cells. However, 90% of the tumors had lost the normal copy of the Min gene, a condition known as loss of heterozygosity (LOH). Foxl1 is a transcription factor expressed in mesenchymal cells adjacent to gastrointestinal epithelial cells, and although mice lacking just Foxl1 show increased β-catenin accumulation in epithelial cells, they do not develop cancer. However, additional deletion of Foxl1 did not enhance nuclear β-catenin accumulation in Min-deficient mice, pointing to LOH as the molecular basis for increased tumor development. The authors suggest that Foxl1 expressed in mesenchymal cells acts as a genetic modifier of the Min gene in gastroepithelial cells and that contribution of the stroma may play an important role in the initiation of gastrointestinal tumors in humans.
N. Perreault, S. D. Sackett, J. P. Katz, E. E. Furth, K. H. Kaestner, Foxl1 is a mesenchymal Modifier of Min in carcinogenesis of stomach and colon. Genes Devel. 19, 311-315 (2005). [Abstract] [Full Text]
Citation: Trans-Cellular Genetic Modification in Cancer. Sci. STKE 2005, tw53 (2005).
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