Apc Deficiency Is Associated with Increased Egfr Activity in the Intestinal Enterocytes and Adenomas of C57BL/6J-Min/+ Mice

Moran, Amy E.; Hunt, Daniel H.; Javid, Sara H.; Redston, Mark; Carothers, Adelaide M.; Bertagnolli, Monica M.

doi:10.1074/jbc.m404276200

Cited by 98 publications

(102 citation statements)

References 90 publications

(86 reference statements)

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“…We observed that mouse tumors that were initiated by inactivation of the Apc gene have phosphorylated S6. There is evidence to suggest that the PI3K and mTOR pathways are activated by default in Apc mutant mice, perhaps resulting in oncogenic addiction to mTOR activation (22,30). However, with the additional incorporation of an activated Kras allele, we find a significant increase in phosphorylated ERK.…”

Section: Discussioncontrasting

confidence: 41%

Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment

Hung

Maricevich

Richard

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

182

236

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Most genetically engineered mouse (GEM) models for colon cancer are based on tissuewide or germline gene modification, resulting in tumors predominantly of the small intestine. Several of these models involve modification of the adenomatous polyposis coli (Apc) gene and are excellent models for familial cancer predisposition syndromes. We have developed a stochastic somatic mutation model for sporadic colon cancer that presents with isolated primary tumors in the distal colon and recapitulates the entire adenoma-carcinoma-metastasis axis seen in human colon cancer. Using this model, we have analyzed tumors that are either solely mutant in the Apc gene or in combination with another colon cancer-associated mutant gene, the Kras G12D allele. Because of the restricted location in the distal colon, the natural history of the tumors can be analyzed by serial colonoscopy. As the mammalian target of rapamycin (mTOR) pathway is a critical component of the complex signaling network in colon cancer, we used this model to assess the efficacy of mTOR blockade through rapamycin treatment of mice with established tumors. After treatment, Apc mutant tumors were more than 80% smaller than control tumors. However, tumors that possessed both Apc and Kras mutations did not respond to rapamycin treatment. These studies suggest that mTOR inhibitors should be further explored as potential colorectal cancer therapies in patients whose tumors do not have activating mutations in KRAS.colon cancer | mouse model | adenovirus | colonoscopy | mammalian target of rapamycin C olon cancer continues to be one of the leading causes of cancerrelated deaths. The prognosis for patients with early stage cancers is good, but the majority of cancers are diagnosed at later stages (1). Most drug development strategies use transplantation of human tumor cells into immunocompromised mice. These models are not truly predictive of response in human patients because they are derived from tumor cell lines grown in vitro and are implanted into ectopic sites that bear no resemblance to the colonic microenvironment (2). Furthermore, these xenograft models fail to recapitulate the heterogeneous nature of cancer and the critical endogenous interplay between tumor and supporting stroma. Genetically engineered mouse (GEM) models circumvent these shortcomings, making them an attractive platform for biomarker discovery, study of cancer biology, and preclinical therapeutic trials (2, 3).Several GEMs that use germline or tissuewide modification of genes known to be mutated in human colon cancer spontaneously develop intestinal tumors (4). Depending on the gene(s) that is modified, these are reasonable models for inherited cancer predisposition syndromes, such as familial adenomatous polyposis (FAP) and hereditary nonpolyposis colon cancer (HNPCC). However, these are not models for sporadic colon cancer, which comprises 75-80% of all cases in humans (5). In these mouse models for FAP and HNPCC, the genetic mutations are present in the germline. Consequently, they are exp...

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Section: Discussioncontrasting

confidence: 41%

Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment

Hung

Maricevich

Richard

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

182

236

View full text Add to dashboard Cite

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“…Furthermore, COX-2 is elevated in colorectal cancers [41], with 50% of adenomas and 80-90% of adenocarcinomas exhibiting increased COX-2 expression, and elevated PGE 2 and 6-keto PGF 1α levels [42,43]. However, conflicting data exist regarding the localization of COX-2 in the epithelium or stromal components of colorectal tumors.…”

Section: Role Of Eicosanoids In the Control Of Intestinal Epithelial mentioning

confidence: 97%

Role of eicosanoids on intestinal epithelial homeostasis

Ferrer

Moreno

2010

Biochemical Pharmacology

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The intestinal epithelium is a highly dynamic system that is continuously renewed by a process involving cell proliferation and differentiation. Moreover, it is the main interface with the external environment, and maintenance and regulation of the epithelial structure and epithelial barrier function are key determinants of digestive health and host well-being. The tight junction, a multiprotein complex composed of transmembrane proteins associated with the cytoskeletal peri-junctional ring of actin and myosin, is an essential component of this barrier that is strictly regulated in a spatio-temporal manner by a complex signaling network. Defects in the intestinal epithelial barrier function have been observed in inflammatory bowel disease, and a classic example of the connection between inflammation and cancer is the increased risk of colorectal cancer in patients with inflammatory bowel disease. In recent years, several molecules have emerged as critical players contributing to inflammationassociated colorectal cancer. For example, eicosanoids derived from arachidonic acid are proposed as mediators involved in the regulation of epithelial structure/function. Interestingly, the tissue concentration of eicosanoids increases during mucosal inflammation and colorectal cancer development. This overview focuses on the physiological and physiopathological roles of eicosanoids in cell growth/cell differentiation/apoptosis and in the paracellular permeability of the intestinal epithelium. A better understanding of these processes will foster new ideas for the development of therapies for these chronic disorders.

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“…Apc Min mice harbor a nonsense APC mutation and spontaneously develop preinvasive adenomas that recapitulate many aspects of the human syndrome, familial adenomatous polyposis coli. Previous reports suggest that EGFR activity is elevated in Apc Min adenoma tissue (22), and introduction of hypomorphic Egfr reduces Apc Min tumor burden by 10-fold (22,23). Moreover, progression of these tumors requires PGE 2 (24,25).…”

Section: Egf Represses Transcription Of Pgdhmentioning

confidence: 99%

Repression of Prostaglandin Dehydrogenase by Epidermal Growth Factor and Snail Increases Prostaglandin E2 and Promotes Cancer Progression

Mann¹,

Backlund

Buchanan

et al. 2006

Cancer Research

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Prostaglandin E 2 (PGE 2 ), a proinflammatory bioactive lipid, promotes cancer progression by modulating proliferation, apoptosis, and angiogenesis. PGE 2 is a downstream product of cyclooxygenase (COX) and is biochemically inactivated by prostaglandin dehydrogenase (PGDH). In the present study, we investigated the mechanisms by which PGDH is downregulated in cancer. We show that epidermal growth factor (EGF) represses PGDH expression in colorectal cancer cells. EGF receptor (EGFR) signaling induces Snail, which binds conserved E-box elements in the PGDH promoter to repress transcription. Induction of PGE 2 catabolism through inhibition of EGFR signaling blocks cancer growth in vivo. In human colon cancers, elevated Snail expression correlates well with down-regulation of PGDH. These data indicate that PGDH may serve a tumor suppressor function in colorectal cancer and provide a possible COX-2-independent way to target PGE 2 to inhibit cancer progression. (Cancer Res 2006; 66(13): 6649-56)

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Apc Deficiency Is Associated with Increased Egfr Activity in the Intestinal Enterocytes and Adenomas of C57BL/6J-Min/+ Mice

Cited by 98 publications

References 90 publications

Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment

Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment

Role of eicosanoids on intestinal epithelial homeostasis

Repression of Prostaglandin Dehydrogenase by Epidermal Growth Factor and Snail Increases Prostaglandin E2 and Promotes Cancer Progression

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