Importance of epidermal growth factor receptor signaling in establishment of adenomas and maintenance of carcinomas during intestinal tumorigenesis

Abstract

We used the hypomorphic Egfr wa2 allele to genetically examine the impact of impaired epidermal growth factor receptor (Egfr) signaling on the Apc Min mouse model of familial adenomatous polyposis. Transfer of the Apc Min allele onto a homozygous Egfr wa2 background results in a 90% reduction in intestinal polyp number relative to Apc Min mice carrying a wild-type Egfr allele. This Egfr effect is potentially synergistic with the actions of the modifierof-min (Mom1) locus. Surprisingly, the size, expansion, and pathological progression of the polyps appear Egfr-independent. Histological examination of the ilea of younger animals revealed no differences in the number of microadenomas, the presumptive precursor lesions to gross intestinal polyps. Pharmacological inhibition with EKI-785, an Egfr tyrosine kinase inhibitor, produced similar results in the Apc Min model. These data suggest that normal Egfr activity is required for establishment of intestinal tumors in the Apc Min model between initiation and subsequent expansion of initiated tumors. The role of Egfr signaling during later stages of tumorigenesis was examined by using nude mice xenografts of two human colorectal cancer cell lines. Treatment with EKI-785 produced a dose-dependent reduction in tumor growth, suggesting that Egfr inhibitors may be useful for advanced colorectal cancer treatment. E pidermal growth factor receptor (Egfr) is the prototypical member of the Erbb family of ligand-activated receptor tyrosine kinases (1). Mice homozygous for the targeted null Egfr tm1Mag allele show strain-dependent lethality (2). Genetic backgrounds supporting survival of Egfr tm1Mag homozygous mutants to term demonstrate the importance of Egfr for epithelial homeostasis (2-4); neonatal mice lacking Egfr maintain a robust proliferative compartment but develop disorganized cryptal architecture of the lower gastrointestinal (GI) tract (2) and hemorrhagic enteritis (4). The hypomorphic Egfr wa2 allele contains a single nucleotide mutation producing a valine to glycine amino acid substitution in the kinase domain, resulting in up to a 90% reduction in kinase activity (5,6 mice exhibit delayed intestinal adaptation and reestablishment of epithelial homeostasis after intestinal resection (7) as well as increased susceptibility to dextran sulfate-induced colitis (8). Furthermore, ectopic Egfr activation promotes increased intestinal epithelial cell proliferation and crypt size but a decrease in crypt fission rates (9).Overexpression of Egfr, the most commonly observed cancerassociated misregulation in Egfr signaling, correlates with poor prognosis in a number of cancers including breast, ovarian, and head and neck (10-12). Because Egfr activation can promote proliferation and maintain survival, amplification of receptor signaling by means of overexpression may promote tumor growth and resistance to apoptosis. Egfr signaling up-regulates its cognate ligands, creating autocrine loops that maintain and amplify levels of Egfr activity (13). For instance, although Egfr activi...

Molecular determination of epidermal growth factor receptor in normal and neoplastic colorectal mucosa

“…The fact that the mean EGFr content is higher in normal mucosa than in neoplastic tissue, both for protein and mRNA determination, does not exclude a role for EGFr in the carcinogenesis of CRC. Epidermal growth factor receptor signalling in the maintenance of carcinomas during intestinal tumorigenesis has been found in animal experiments (Roberts et al, 2002). In our study, the inverse relationship between EGFr expression and activity, demonstrated so far in CRC cell lines (Keese et al, 2005), supports the hypothesis that activated EGFr has a role in CRC.…”

Genomic instability and oncogene amplifications in colorectal adenomas predict recurrence and synchronous carcinoma

“…However, overexpression causes apoptotic resistance and tumor propagation, especially in colorectal carcinogenesis. 23,24 Therefore, our finding of EGFR amplifications seems to identify cells that drive tumor formation and propagation. Interestingly, such amplifications were accompanied by deletions of SMAD7.…”

Lack of guanylyl cyclase C, the receptor for Escherichia coli heat‐stable enterotoxin, results in reduced polyp formation and increased apoptosis in the multiple intestinal neoplasia (Min) mouse model

“…40,41 In Apc Min/1 mice expressing a mutant epidermal growth factor receptor, polyp number was reduced 90% compared to mice with wild-type receptor. 42 In a mouse xenograft model, treatment with an inhibitor of the upstream kinase MEK suppressed tumor growth, 43 providing further evidence of the importance of the ERK signaling pathway in colon cancer. The impact of GC-C deficiency on this pathway may be one of the alterations leading to increased apoptosis in the intestine of Apc Min/1 ; Gucy2c 2/2 mice.…”