APC and Oncogenic KRAS Are Synergistic in Enhancing Wnt Signaling in Intestinal Tumor Formation and Progression

Janssen, Klaus–Peter; Alberici, Paola; Fsihi, Hafida; Gaspar, Cláudia; Breukel, Cor; Franken, Patrick; Rosty, Christophe; Abal, Miguel; Marjou, Fatima El; Smits, Ron; Louvard, Daniel; Fodde, Riccardo; Robine, Sylvie

doi:10.1053/j.gastro.2006.08.011

Cited by 255 publications

(274 citation statements)

References 53 publications

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“…Histologic analysis did reveal that the addition of the Kras allele promotes the progression from adenomas to carcinomas and metastasis. Similar findings have been reported in Apc/Kras-based mouse models by other groups, as well (23)(24)(25). Interestingly, whereas the multiplicity of the tumors in the Apc CKO/LSL-Kras mice increased threefold, the overall growth rate of the established tumors was not increased significantly.…”

Section: Discussionsupporting

confidence: 89%

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.

180

234

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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: Discussionsupporting

confidence: 89%

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.

180

234

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“…According to the Vogelstein model, the initiating APC or CTNNB1 mutation is often followed by oncogenic activation of the KRAS gene (5). The number of visible tumors is highly increased when the mutant KRas gene is introduced to the Apc 1638N/+ (ApcN) mice that otherwise have only few intestinal tumors (22). We cultured organoids from the intestines of ApcN and ApcN-KRas mice in conditions in which only the Apc-mutant organoids survive.…”

Section: Mutant Kras Oncogene Protects Apc-mutant Organoids From Tgf-mentioning

confidence: 99%

Oncogenic mutations in intestinal adenomas regulate Bim-mediated apoptosis induced by TGF-β

Wiener

Band

Kallio

et al. 2014

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

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In the majority of microsatellite-stable colorectal cancers (CRCs), an initiating mutation occurs in the adenomatous polyposis coli (APC) or β-catenin gene, activating the β-catenin/TCF pathway. The progression of resulting adenomas is associated with oncogenic activation of KRas and inactivation of the p53 and TGF-β/Smad functions. Most established CRC cell lines contain mutations in the TGF-β/Smad pathway, but little is known about the function of TGF-β in the early phases of intestinal tumorigenesis. We used mouse and human ex vivo 3D intestinal organoid cultures and in vivo mouse models to study the effect of TGF-β on the Lgr5 + intestinal stem cells and their progeny in intestinal adenomas. We found that the TGF-β-induced apoptosis in Apc-mutant organoids, including the Lgr5 + stem cells, was mediated by up-regulation of the BH3-only proapoptotic protein Bcl-2-like protein 11 (Bim). BH3-mimetic compounds recapitulated the effect of Bim not only in the adenomas but also in human CRC organoids that had lost responsiveness to TGF-β-induced apoptosis. However, wild-type intestinal crypts were markedly less sensitive to TGF-β than Apcmutant adenomas, whereas the KRas oncogene increased resistance to TGF-β via the activation of the Erk1/2 kinase pathway, leading to Bim down-regulation. Our studies identify Bim as a critical mediator of TGF-β-induced apoptosis in intestinal adenomas and show that the common progression mutations modify Bim levels and sensitivity to TGF-β during intestinal adenoma development.A ctivation of the β-catenin/TCF transcription factor (Wnt) pathway is the initiating event in the majority of human colorectal cancers (CRCs) and one of the key regulators of CRC pathogenesis (1, 2). The β-catenin level in cells is controlled through a multiprotein complex that contains the adenomatous polyposis coli (APC) protein. In 70-80% of individuals suffering from the sporadic version of CRC, both APC alleles are mutated and thus inactivated, resulting in elevated nuclear β-catenin levels (1). Recently, the intestinal stem cells have been identified as the cells of origin of CRC (3, 4).According to the model presented by Fearon and Vogelstein (5), the initiating APC or CTNNB1 mutation is followed by oncogenic activation of the KRAS gene and inactivation of the TGF-β signal transduction pathway and the TP53 tumor suppressor. Recent genome-wide analysis by the Cancer Genome Atlas Network has demonstrated the high frequency of mutations in the β-catenin/TCF, TGF-β, phosphoinositide 3-kinase (PI3K) and p53 pathways in CRC (6). Full understanding of the roles of the driver mutations in colorectal tumors has been hampered by lack of appropriate ex vivo model systems for studies of CRC progression, and thus it has been difficult to study the effects of TGF-β in intestinal adenoma cells at the early stages of tumor development. Although TGF-β receptors have been deleted in Apc-mutant mouse models of CRC (7,8), these studies do not reveal the mechanism of TGF-β action in intestinal adenomas or give further i...

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“…Given that colorectal tumours from Apc/Kras compound mutant mice develop features of early-stage malignant progression 8,10,11 , we sought to utilize these tumours in an attempt to develop a reproducible model of metastatic CRC for investigating routes of metastatic dissemination. We generated Apc Min/ þ ; Kras LSLG12D/ þ ;Villin-Cre compound mutant mice (mice carrying a Cre-dependent activated allele of Kras (Kras LSLG12D ) on the Apc Min/ þ background, crossed with mice carrying a Villin-Cre transgene that directs expression of Cre recombinase throughout the intestine), and confirmed an enhancement of tumour development in the colon compared with Apc Min/ þ ; Villin-Cre control mice ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Introduction of oncogenic Kras to the mutant Apc background promotes intestinal adenoma multiplicity 8,9 and accelerates progression to invasiveness 8,10,11 , with a marked enhancement of tumour development in the relevant anatomical location of the colon 9 . Development of intestinal lymph node metastases, however, has not been observed in Apc/Kras compound mutant mice 8,12 , with distant liver metastases only detected in 20-27% of Apc/Kras compound mutant mice by transgene RT-PCR 8 or gross observation 12 . Of note, Apc/Kras compound mutant mice exhibit a dramatically reduced lifespan, which can be attributed to intestinal tumour overburden 9,10 .…”

mentioning

confidence: 99%

“…Given that Apc/Kras compound mutant tumours exhibit features of early-stage malignant progression 8,10,11 , we postulated that maintaining a compound mutant tumour in vivo beyond the shortened lifespan of an Apc/Kras mutant mouse might enable a realization of metastatic potential. We therefore sought to transplant a single intact Apc/Kras compound mutant donor tumour within the mucosal layer of a host wildtype C57BL/6J mouse colon, as this would faithfully represent an orthotopic primary colorectal tumour at clinical stage 0 (in situ carcinoma) with the potential to progress to stage IV disease.…”

mentioning

confidence: 99%

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Lymph node-independent liver metastasis in a model of metastatic colorectal cancer

Enquist¹,

Good²,

Jubb³

et al. 2014

Nat Commun

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Deciphering metastatic routes is critically important as metastasis is a primary cause of cancer mortality. In colorectal cancer (CRC), it is unknown whether liver metastases derive from cancer cells that first colonize intestinal lymph nodes, or whether such metastases can form without prior lymph node involvement. A lack of relevant metastatic CRC models has precluded investigations into metastatic routes. Here we describe a metastatic CRC mouse model and show that liver metastases can manifest without a lymph node metastatic intermediary. Colorectal tumours transplanted onto the colonic mucosa invade and metastasize to specific target organs including the intestinal lymph nodes, liver and lungs. Importantly, this metastatic pattern differs from that observed following caecum implantation, which invariably involves peritoneal carcinomatosis. Anti-angiogenesis inhibits liver metastasis, yet anti-lymphangiogenesis does not impact liver metastasis despite abrogating lymph node metastasis. Our data demonstrate direct hematogenous spread as a dissemination route that contributes to CRC liver malignancy.

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APC and Oncogenic KRAS Are Synergistic in Enhancing Wnt Signaling in Intestinal Tumor Formation and Progression

Cited by 255 publications

References 53 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

Oncogenic mutations in intestinal adenomas regulate Bim-mediated apoptosis induced by TGF-β

Lymph node-independent liver metastasis in a model of metastatic colorectal cancer

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