Abstract
The first step in the development of human colorectal cancer is aberrant activation of the Wnt signaling pathway. Wnt signaling hyperactivation is predominantly caused by loss-of-function mutations in the adenomatous polyposis coli (APC) gene that encodes the pathway negative regulator. In order to identify genes affected by the Apc loss, we performed expression profiling of intestinal epithelium isolated from mice harboring a conditional Apc allele. The gene encoding transcriptional factor msh homeobox 1 (Msx1) displayed robust upregulation upon Apc inactivation. Histological analysis of the Apc-deficient epithelium revealed that in the small intestine, the Msx1 protein was localized exclusively in ectopic crypts, i.e., in pockets of proliferating cells abnormally positioned on the villi. Ablation of the Msx1 gene leads to the disappearance of ectopic crypts and loss of differentiated cells. Moreover, tumors arising from Msx1-deficient cells display altered morphology reminiscent of villous adenomas. In human tumor specimens, MSX1 displayed significantly increased expression in colonic neoplasia with a descending tendency during the lesion progression towards colorectal carcinoma. In summary, the results indicate that Msx1 represents a novel marker of intestinal tumorigenesis. In addition, we described the previously unknown relationship between the Msx1-dependent formation of ectopic crypts and cell differentiation.
Highlights
The first step in the development of human colorectal cancer is aberrant activation of the Wnt signaling pathway
The homeostasis of the tissue is sustained by multipotent intestinal stem cells (ISCs) that reside at the bottom of submucosal invaginations of the single-layer epithelium called the crypts of Lieberkühn
We aimed to identify and characterize the genetic program related to cell transformation induced by the loss of the Apc tumor suppressor gene
Summary
The first step in the development of human colorectal cancer is aberrant activation of the Wnt signaling pathway. Basic information about the genetic program controlled by the Wnt/β-catenin pathway in the intestine was obtained by studying tumor cells derived from cancer affecting the colon and rectum. The majority (>80%) of sporadic colorectal tumors contain mutations in the tumor suppressor adenomatous polyposis coli (APC) gene, which encodes the negative regulator of canonical Wnt signaling[6]. Aberrant (hyper)activation of the Wnt pathway in the mouse intestinal epithelium using homozygous deletion of the Apc gene or β-catenin stabilization instantly promotes cellular proliferation while impairing differentiation[7,8,9]. In 2002, van de Wetering and colleagues identified leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) as a gene upregulated by aberrant Wnt signaling in human colon cancer cells. Subsequent lineage tracing experiments performed in genetically modified mice revealed that Lgr[5] is produced in ISCs10
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