Name: a genetically engineered mouse model of sporadic colorectal cancer
Uploaded: 2017-07-06T12:30:00
Description: Watch this Scientific Journal Video about A Genetically Engineered Mouse Model of Sporadic Colorectal Cancer at JoVE.com

This work is dedicated to the memory of Professor Moritz Koch.

The animal experiments presented here were independently reviewed and approved by an institutional and a governmental Animal Care and Use Committee and were conducted according to Federation of Laboratory Animal Science Associations (FELASA) guidelines. All possible measures were taken to minimize suffering including anesthesia and analgesia or, if necessary, premature euthanasia.
1. Local Tumor Induction via Surgical Adeno-cre Infection
<ol>
	<li>Preparation of animals for ...

<ol>
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D., Jemal, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Cancer+statistics,+2016.">Cancer statistics, 2016.</a> CA Cancer J Clin. 66 (1), 7-30 (2016).</li><li>Weitz, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Colorectal+cancer.">Colorectal cancer.</a> Lancet. 365 (9454), 153-165 (2005).</li><li>Bork, U., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Prognostic+relevance+of+minimal+residual+disease+in+colorectal+cancer.">Prognostic relevance of minimal residual disease in colorectal cancer.</a> World J Gastroenterol. 20 (30), 10296-10304 (2014).</li><li>Steinert, G., Sch&#246;lch, S., Koch, M., Weitz, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Biology+and+significance+of+circulating+and+disseminated+tumour+cells+in+colorectal+cancer.">Biology and significance of circulating and disseminated tumour cells in colorectal cancer.</a> Langenbecks Arch Surg. 397 (4), 535-542 (2012).</li><li>Garc&#237;a, S. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=LDB1+overexpression+is+a+negative+prognostic+factor+in+colorectal+cancer.">LDB1 overexpression is a negative prognostic factor in colorectal cancer.</a> Oncotarget. 7 (51), 84258-84270 (2016).</li><li>van Noort, V., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Novel+Drug+Candidates+for+the+Treatment+of+Metastatic+Colorectal+Cancer+through+Global+Inverse+Gene-Expression+Profiling.">Novel Drug Candidates for the Treatment of Metastatic Colorectal Cancer through Global Inverse Gene-Expression Profiling.</a> Cancer Res. 74 (20), 5690-5699 (2014).</li><li>Nanduri, L. K., Garc&#237;a, S., Weitz, J., Sch&#246;lch, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mouse+Models+of+Colorectal+Cancer-Derived+Circulating+Tumor+Cells.">Mouse Models of Colorectal Cancer-Derived Circulating Tumor Cells.</a> Med Chem (Los Angeles). 6 (7), 497-499 (2016).</li><li>Taketo, M. M., Edelmann, W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mouse+models+of+colon+cancer.">Mouse models of colon cancer.</a> Gastroenterology. 136 (3), 780-798 (2009).</li><li>Sch&#246;lch, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Circulating+tumor+cells+exhibit+stem+cell+characteristics+in+an+orthotopic+mouse+model+of+colorectal+cancer.">Circulating tumor cells exhibit stem cell characteristics in an orthotopic mouse model of colorectal cancer.</a> Oncotarget. 7 (19), 27232-27242 (2016).</li><li>Sch&#246;lch, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Radiotherapy+combined+with+TLR7/8+activation+induces+strong+immune+responses+against+gastrointestinal+tumors.">Radiotherapy combined with TLR7/8 activation induces strong immune responses against gastrointestinal tumors.</a> Oncotarget. 6 (7), 4663-4676 (2015).</li><li>Corbett, T. H., Griswold, D. P., Roberts, B. J., Peckham, J. C., Schabel, F. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Tumor+induction+relationships+in+development+of+transplantable+cancers+of+the+colon+in+mice+for+chemotherapy+assays,+with+a+note+on+carcinogen+structure.">Tumor induction relationships in development of transplantable cancers of the colon in mice for chemotherapy assays, with a note on carcinogen structure.</a> Cancer Res. 35 (9), 2434-2439 (1975).</li><li>Roper, J., Hung, K. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Priceless+GEMMs:+genetically+engineered+mouse+models+for+colorectal+cancer+drug+development.">Priceless GEMMs: genetically engineered mouse models for colorectal cancer drug development.</a> Trends Pharmacol Sci. 33 (8), 449-455 (2012).</li><li>Hung, K. E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=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.</a> Proc Natl Acad Sci USA. 107 (4), 1565-1570 (2010).</li><li>Sharpless, N. E., Depinho, R. 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F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=High+resolution+colonoscopy+in+live+mice.">High resolution colonoscopy in live mice.</a> Nat Protoc. 1 (6), 2900-2904 (2006).</li><li>Moser, A. R., Pitot, H. C., Dove, W. 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While they are generally easy to generate and maintain, classical CRC mouse models based on cell line injection are artificial and are not able to fully recapitulate the human disease. As a consequence, GEMMs have been developed. The first CRC GEMM was the ApcMin mouse, which harbors a heterozygous null mutation in the Apc gene, therefore mimicking the human hereditary disease familial adenomatous polyposis (FAP).21 However, ApcMin mice invariably develop multiple intestinal ...

Colorectal cancer (CRC) continues to be one of the leading causes of cancer-related death in western countries.1 While the prognosis of patients with early stage disease is good, many tumors are diagnosed at later stages in which, despite numerous treatment options, the prognosis is limited.2,3,4,5
The majority of current mouse models of CRC are based on the implantation of tumor cells derived from cell lines or patient tumors into immunodeficient mice.6,7,8 This leads to local and, depending on the injection site and the tumor cells used for injection, sometimes metastatic tumors.9,10 However, the resulting xenograft models have major limitations. They must be established in immunodeficient mice, thus eliminating the complex interaction between the tumor and the host immune system. In addition, as the tumor stroma is derived from host cells, the interaction between human tumor parenchyma and murine stroma is defective and therefore not representative of the disease. These deficiencies can be avoided by the use of murine cell lines for injection. However, only few murine CRC cell lines are available and, similar to most available human CRC cell lines, are monoclonal and highly anaplastic.11 In summary, most currently available CRC mouse models are highly artificial and not fully representative of the human disease.
Genetically engineered mouse models (GEMMs) of CRC can avoid these drawbacks as they feature genuine mouse tumors which are created via induction of key mutations of CRC in the colon.12,13,14 This can be achieved by the activation of conditional (floxed) germline mutations by cre recombinase within the colorectal mucosa. While in GEMMs of many other tumor entities germline (inducible) cre expression driven by tissue-specific promoters is used, germline cre cannot be used in the colon as this leads to a great number of adenomas throughout the colon causing death by benign tumor load at a very young age. Therefore, in the here described model an adenoviral vector expressing cre is used to infect a short colon segment. This leads to the induction of tumorigenesis within this segment of the mucosa at a time point defined by the investigator, resulting in adenomas ultimately progressing to invasive and metastatic carcinoma. The tumors are genuine mouse tumors, grow in an intact microenvironment and are therefore able to simulate the entirety of colorectal oncogenesis including tumor&#8211;host interaction and the metastatic cascade. This model is therefore an attractive platform for studies of cancer biology and preclinical therapeutic trials.
A major disadvantage of genetically engineered mouse models of CRC is their technical complexity. Local cre delivery using rectal adeno-cre enemas in mice carrying floxed Apc alleles has been described before; however, the incidence, multiplicity and location of the intestinal tumors can be highly variable with this technique.15 Therefore, the technique of confining the adeno-cre infection by surgical clamping of the segment to be induced has been developed.13 We have modified this procedure in order to improve animal welfare, as well as reduce mortality and the number of resulting tumors. With this protocol, all labs with experience in small rodent surgery should be able to reproduce the model and to produce tumors which are highly reproducible and easily accessible to colonoscopy. Depending on the conditional mutations used for tumorigenesis, the full spectrum of adenoma, invasive carcinoma and metastases can be observed. As the tumors are located in the distal colon, serial endoscopic assessment is easily possible in this model.

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			<td>Reagents / consumables</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Dulbecco&#39;s Phosphate Buffered Saline</td>
			<td>Life Technologies GmbH</td>
			<td>14190169</td>
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			<td>Trypsin-EDTA (0.25%, Phenol-Red)</td>
			<td>Life Technologies GmbH</td>
			<td>25200072</td>
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			<td>Normal saline 0.9% (E154)</td>
			<td>Serumwerk Bernburg AG</td>
			<td>10013</td>
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			<td>Aqua ad injectabilia</td>
			<td>B. Braun Melsungen AG</td>
			<td>235144</td>
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			<td>Ad5CMV-Cre (adenovirus, c = 2E+11 PFU/mL)</td>
			<td>Gene Transfer Vector Core 
			University of Iowa</td>
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			<td>15 mL, 50 mL centrifuge tubes</td>
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			<td>188271/227270</td>
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			<td>Eppendorf tubes 1.5 mL/ 2 mL</td>
			<td>Sarstedt AG &#38; Co.</td>
			<td>72,695,400</td>
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			<td>Petri dish PS 100/15 mm (sterile, Nuclon)</td>
			<td>Fisher Scientific GmbH</td>
			<td>10508921/ NUNC150350</td>
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			<td>Braun/neoLab</td>
			<td>194291661</td>
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			<td>30G injection needle</td>
			<td>BECTON DICKINSON</td>
			<td>304000</td>
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			<td>AbbVie Germany GmbH &#38; Co. KG</td>
			<td>-</td>
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			<td>Medical oxygen</td>
			<td>Air Liquide Medical GmbH</td>
			<td>-</td>
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			<td>Buprenorphine (Temgesic)</td>
			<td>Indivior Eu Ltd.</td>
			<td>-</td>
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			<td>Bepanthen - ophthalmic ointment</td>
			<td>Bayer Vital GmbH</td>
			<td>10047757</td>
			<td></td>
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			<td>Table Top Research Anesthesia Machine x/O2 Flush w/ Sevoflurane Vaporizer</td>
			<td>Parkland Scientific</td>
			<td>V3000PS/PK</td>
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			<td>Name</td>
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			<td>Surgical Equipment</td>
			<td></td>
			<td></td>
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			<td>Cellulose swabs</td>
			<td>Lohmann &#38; Rauscher Deutschland</td>
			<td>13356</td>
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			<td>Insulin syringe EMG 1 mL (with 30G cannula)</td>
			<td>B. Braun Melsungen AG</td>
			<td>9161627S</td>
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			<td>Fine Bore Tubing (bore: 0.28 mm/ diameter: 0.61mm)</td>
			<td>Smiths Medical Deutschland</td>
			<td>800/100/100</td>
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			<td>Micro-Adson Forceps</td>
			<td>Fine Science Tools</td>
			<td>11018-12</td>
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			<td>Iris Scissor - ToughCut</td>
			<td>Fine Science Tools</td>
			<td>14058-11</td>
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			<td>Olsen-Hegar Needle Holder</td>
			<td>Fine Science Tools</td>
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			<td>AutoClip Kit</td>
			<td>Fine Science Tools</td>
			<td>12020-00</td>
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			<td>PDS Z1012H 6/0 C1 (surgical suture)</td>
			<td>Johnson &#38; Johnson Medical GmbH</td>
			<td>Z1012H</td>
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			<td>Curved Micro Serrefine Vascular Clamp</td>
			<td>Fine Science Tools</td>
			<td>18055-05</td>
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			<td>Fogarty Spring Clips</td>
			<td>Edwards</td>
			<td>CDSAFE 6</td>
			<td></td>
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			<td>Hot Plate 062</td>
			<td>Labotect</td>
			<td>13854</td>
			<td></td>
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			<td>Isis - Hair shaver</td>
			<td>Aesculap - Braun</td>
			<td>-</td>
			<td></td>
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		<tr>
			<td>Name</td>
			<td>Company</td>
			<td>Catalog Number</td>
			<td>Comments</td>
		</tr>
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			<td>Colonoscopy</td>
			<td></td>
			<td></td>
			<td></td>
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			<td>Cold Light Fountain XENON 175 SCB</td>
			<td>Karl Storz</td>
			<td>20132101-1</td>
			<td>Karl Storz Coloview System Mainz</td>
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			<td>Fiber Optic Light Cable</td>
			<td>Karl Storz</td>
			<td>69495NL</td>
			<td>Karl Storz Coloview System Mainz</td>
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			<td>TRICAM Three-Chip Camera Head</td>
			<td>Karl Storz</td>
			<td>20221030</td>
			<td>Karl Storz Coloview System Mainz</td>
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			<td>TRICAM SLII Camera Control Unit</td>
			<td>Karl Storz</td>
			<td>20223011-1</td>
			<td>Karl Storz Coloview System Mainz</td>
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			<td>15&#34; Flat Screen Monitor EndoVue</td>
			<td>Karl Storz</td>
			<td>9415NN</td>
			<td>Karl Storz Coloview System Mainz</td>
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			<td>HOPKINS Straight Forward Telescope 
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			autoclavable 
			fiber optic light transmission incorporated</td>
			<td>Karl Storz</td>
			<td>64301AA</td>
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			<td>Protection and Examination Sheath</td>
			<td>Karl Storz</td>
			<td>61029C</td>
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a genetically engineered mouse model of sporadic colorectal cancer

Despite the advantages of easy applicability and cost-effectiveness, colorectal cancer mouse models based on tumor cell injection have severe limitations and do not accurately simulate tumor biology and tumor cell dissemination. Genetically engineered mouse models have been introduced to overcome these limitations; however, such models are technically demanding, especially in large organs such as the colon in which only a single tumor is desired.
As a result, an immunocompetent, genetically engineered mouse model of colorectal cancer was developed which develops highly uniform tumors and can be used for tumor biology studies as well as therapeutic trials. Tumor development is initiated by surgical, segmental infection of the distal colon with adeno-cre virus in compound conditionally mutant mice. The tumors can be easily detected and monitored via colonoscopy. We here describe the surgical technique of segmental adeno-cre infection of the colon, the surveillance of the tumor via high-resolution colonoscopy and present the resulting colorectal tumors.

If performed adequately, &#62; 85% of the animals develop tumors. The mortality of the here presented surgical procedure is &#60; 5%, mortality of the colonoscopy is virtually non-existent. In the majority of mice, a single lesion is detected; in about 30% 2 - 3 small adenomas can be detected which usually fuse to a single tumor within 2 - 3 weeks after tumor induction.
The phenotype and biological behavior of the resulting tumo...

Watch this Scientific Journal Video about A Genetically Engineered Mouse Model of Sporadic Colorectal Cancer at JoVE.com

A Genetically Engineered Mouse Model of Sporadic Colorectal Cancer

A protocol for the establishment of a genetically engineered mouse model of colorectal cancer by segmental adeno-cre infection and its surveillance via high-resolution colonoscopy is presented.

Despite the advantages of easy applicability and cost-effectiveness, colorectal cancer mouse models based on tumor cell injection have severe limitations ...

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Establishing a Competing Risk Regression Nomogram Model for Survival Data

The Kaplan&#8211;Meier method and Cox proportional hazards regression model are the most common analyses in the survival framework. These are relatively ...

Analysis of Lymph Node Volume by Ultra-High-Frequency Ultrasound Imaging in the Braf/Pten Genetically Engineered Mouse Model of Melanoma

Tyr::CreER+,BrafCA/+,Ptenlox/lox&#160;genetically engineered mice (Braf/Pten mice) are widely used as an in vivo model of metastatic melanoma. Once a ...

Portal Vein Injection of Colorectal Cancer Organoids to Study the Liver Metastasis Stroma

Hepatic metastasis of colorectal cancer (CRC) is a leading cause of cancer-related death. Cancer-associated fibroblasts (CAFs), a major component of the ...

Molecular and Immunologic Techniques in a Genetically Engineered Mouse Model of Gastrointestinal Stromal Tumor

Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and is typically driven by a single mutation in the KIT receptor. Across tumor ...