Name: orthotopic implantation of patient-derived cancer cells in mice recapitulates advanced colorectal cancer
Uploaded: 2023-02-10T13:05:00
Description: Watch this Scientific Journal Video about Orthotopic Implantation of Patient-Derived Cancer Cells in Mice Recapitulates Advanced Colorectal Cancer at JoVE.com

We acknowledge the Cellex Foundation, CIBERONC network, and Instituto de Salud Carlos III for their support. Moreover, we also thank the preclinical imaging platform at the Vall d&#39;Hebron Research Institute (VHIR), where the experiments were performed.

Written informed consent was obtained from all patients. The project was approved by the Research Ethics Committee of the Vall d&#39;Hebron University Hospital, Barcelona, Spain (approval ID: PR(IR)79/2009 PR(AG)114/2014, PR(AG)18/2018). Human colon tissue samples consisted of biopsies from non-necrotic areas of primary adenocarcinomas or liver metastases, corresponding to patients with colon and rectal cancer who underwent tumor resection. Experiments were conducted following the European Union&#39;s animal care directi...

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	<li>Sung, H., 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=Global+Cancer+Statistics+2020:+GLOBOCAN+estimates+of+incidence+and+mortality+worldwide+for+36+cancers+in+185+countries.">Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.</a> CA: a Cancer Journal for Clinicians. 71 (3), 209-249 (2021).</li><li>Puig, I., 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=A+personalized+preclinical+model+to+evaluate+the+metastatic+potential+of+patient-derived+colon+cancer+initiating+cells.">A personalized preclinical model to evaluate the metastatic potential of patient-derived colon cancer initiating cells.</a> Clinical Cancer Research. 19 (24), 6787-6801 (2013).</li><li>Clevers, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Modeling+development+and+disease+with+organoids.">Modeling development and disease with organoids.</a> Cell. 165 (7), 1586-1597 (2016).</li><li>Byrne, A. T., 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=Interrogating+open+issues+in+cancer+precision+medicine+with+patient-derived+xenografts.">Interrogating open issues in cancer precision medicine with patient-derived xenografts.</a> Nature Reviews. Cancer. 17 (4), 254-268 (2017).</li><li>Vatandoust, S., Price, T. J., Karapetis, C. S. <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:+Metastases+to+a+single+organ.">Colorectal cancer: Metastases to a single organ.</a> World Journal of Gastroenterology. 21 (41), 11767-11776 (2015).</li><li>Cespedes, M. 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=Orthotopic+microinjection+of+human+colon+cancer+cells+in+nude+mice+induces+tumor+foci+in+all+clinically+relevant+metastatic+sites.">Orthotopic microinjection of human colon cancer cells in nude mice induces tumor foci in all clinically relevant metastatic sites.</a> The American Journal of Pathology. 170 (3), 1077-1085 (2007).</li><li>Durkee, B. Y., Weichert, J. P., Halberg, R. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Small+animal+micro-CT+colonography.">Small animal micro-CT colonography.</a> Methods. 50 (1), 36-41 (2010).</li><li>Boll, H., 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=Double-contrast+micro-CT+colonoscopy+in+live+mice.">Double-contrast micro-CT colonoscopy in live mice.</a> International Journal of Colorectal Disease. 26 (6), 721-727 (2011).</li><li>O'Brien, C. A., Pollett, A., Gallinger, S., Dick, J. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+human+colon+cancer+cell+capable+of+initiating+tumour+growth+in+immunodeficient+mice.">A human colon cancer cell capable of initiating tumour growth in immunodeficient mice.</a> Nature. 445 (7123), 106-110 (2007).</li><li>Jensen, M. M., Jorgensen, J. T., Binderup, T., Kjaer, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Tumor+volume+in+subcutaneous+mouse+xenografts+measured+by+microCT+is+more+accurate+and+reproducible+than+determined+by+18F-FDG-microPET+or+external+caliper.">Tumor volume in subcutaneous mouse xenografts measured by microCT is more accurate and reproducible than determined by 18F-FDG-microPET or external caliper.</a> BMC Medical Imaging. 8, 16 (2008).</li><li>Herpers, B., 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=Functional+patient-derived+organoid+screenings+identify+MCLA-158+as+a+therapeutic+EGFR+x+LGR5+bispecific+antibody+with+efficacy+in+epithelial+tumors.">Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR x LGR5 bispecific antibody with efficacy in epithelial tumors.</a> Nature Cancer. 3 (4), 418-436 (2022).</li><li>Chicote, I., Camara, J. A., Palmer, H. G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Advanced+colorectal+cancer+orthotopic+patient-derived+xenograft+models+for+cancer+and+stem+cell+research.">Advanced colorectal cancer orthotopic patient-derived xenograft models for cancer and stem cell research.</a> Methods in Molecular Biology. 2171, 321-329 (2020).</li></ol>

Over the last few decades, many new anti-cancer therapies have been developed and tested in patients with different tumor types, including colorectal cancer (CRC). Although promising results in preclinical models have been observed in many cases, the therapeutic efficacy in patients with advanced metastatic CRC has been frequently limited. Therefore, there is an urgent need for preclinical models that allow for testing the efficacy of new therapeutic drugs in a clinically relevant metastatic scenario.
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Colorectal cancer (CRC) is the second leading cause of cancer death worldwide1. The ability to generate in vitro or in vivo tumor models derived from individual patient tumor cells has advanced precision medicine in oncology. Over the last decade, patient derived organoids (PDOs) or xenografts (PDXs) have been used by many research groups around the world2. PDOs are multicellular in vitro structures that resemble the features of the original tumor tissue and can self-organize and self-renew3. These promising in vitro models can successfully be used for drug screening and facilitating translational research. On the other side, PDX models faithfully recapitulate the original CRC at all relevant levels, from histology to molecular traits and drug response2,4.
In vivo PDX models are mostly grown as subcutaneous tumors in immunodeficient mice. Using this approach, PDXs have become the gold standard in cancer research, particularly for studying drug sensitivity or resistance. However, CRC related deaths are mostly associated with the presence of metastatic lesions in the liver, the lung, or the peritoneal cavity, and neither of the two approaches (PDO or PDX) can recapitulate the advanced clinical setting. In addition, the specific site of tumor growth has been shown to determine important biological characteristics that have an impact on drug efficacy and disease prognosis2. Therefore, there is an urgent need to establish preclinical models that can be used to assess the efficacy of anticancer drugs in a clinically relevant metastatic setting6.
Microcomputed tomography (&#181;CT) scanners can function as scaled-down clinical CT scanners, providing primary tumor and metastasis imaging in mice at a scaled image resolution proportional to that of CT images of cancer patients7. To counteract the poor soft tissue contrast of the &#181;CT technique, radiological iodinated contrast agents can be used to improve the contrast and evaluate tumor burden. Using a dual contrast approach, oral and intraperitoneal iodine is administrated at different timings. The contrast administrated orally helps to define the limits between tumor tissue and cecum content inside the bowel. &#160;On the other side, the contrast administered intraperitoneally allows for the identification of the external limits of the tumor mass, which frequently grows and invades the peritoneum8.
The manuscript describes a protocol to perform orthotopic implantation of patient-derived cancer cells in the cecum wall of immunodeficient mice, and the methodology to monitor intestinal tumor growth using &#181;CT scanning. The present manuscript shows that the model recapitulates the clinical scenario of advanced intestinal tumors and metastatic disease in CRC patients that cannot be studied using PDO or PDXO models. Since orthotopic PDX models of CRC recapitulate the clinical scenario of CRC patients, we conclude that they are the best to date for testing the efficacy of anti-tumoral drugs in advanced intestinal tumors and metastatic disease.

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orthotopic implantation of patient-derived cancer cells in mice recapitulates advanced colorectal cancer

Over the last decade, more sophisticated preclinical colorectal cancer (CRC) models have been established using patient-derived cancer cells and 3D tumoroids. Since patient derived tumor organoids can retain the characteristics of the original tumor, these reliable preclinical models enable cancer drug screening and the study of drug resistance mechanisms. However, CRC related death in patients is mostly associated with the presence of metastatic disease. It is therefore essential to evaluate the efficacy of anti-cancer therapies in relevant in vivo models that truly recapitulate the key molecular features of human cancer metastasis. We have established an orthotopic model based on the injection of CRC patient-derived cancer cells directly into the cecum wall of mice. These tumor cells develop primary tumors in the cecum that metastasize to the liver and lungs, which is frequently observed in patients with advanced CRC. This CRC mouse model can be used to evaluate drug responses monitored by microcomputed tomography (&#181;CT), a clinically relevant small-scale imaging method that can easily identify primary tumors or metastases in patients. Here, we describe the surgical procedure and the required methodology to implant patient-derived cancer cells in the cecum wall of immunodeficient mice.

Mice orthotopically implanted with patient-derived cancer cells were monitored weekly by &#181;CT scanning. At the end of the experiment, the animals were euthanized. Intestines, ceca (Figure 1A,B), livers, lungs,&#160;and any other possible lesion were collected, included in a cassette, and fixed with 4% formalin overnight. Intestine tissue from a mouse without a tumor in the cecum was used as a control (Figure 1C). Finally, cassettes were chan...

Watch this Scientific Journal Video about Orthotopic Implantation of Patient-Derived Cancer Cells in Mice Recapitulates Advanced Colorectal Cancer at JoVE.com

Orthotopic Implantation of Patient-Derived Cancer Cells in Mice Recapitulates Advanced Colorectal Cancer

This protocol describes the orthotopic implantation of patient-derived cancer cells in the cecum wall of immunodeficient mice. The model recapitulates advanced colorectal cancer metastatic disease and allows for the evaluation of new therapeutic drugs in a clinically relevant scenario of lung and liver metastases.

Over the last decade, more sophisticated preclinical colorectal cancer (CRC) models have been established using patient-derived cancer cells and 3D ...

This protocol describes the orthotopic implantation of patient-derived cancer cells in the cecum wall of immunodeficient mice. This model recapitulates advanced colorectal cancer metastatic disease. The orthotopic colorectal cancer model presented here recapitulates the clinical scenario of advanced intestinal tumors and metastatic disease in colorectal cancer patients that cannot be studied using patient-derived organoids or patient-derived xenograft models.From a euthanized mouse, extract the tumor by carefully removing it from the skin and surrounding non-tumor tissue using scissors and forceps. Place the harvested tumors in PBS at four degrees Celsius. Using a blade, dissociate the tumors in a 10-centimeter culture plate containing one-millimeter of medium.Place the homogeneous dissociated sample into a 15-milliliter conical tube. Then, add the medium to a final volume of five milliliters. Then, add the digestion medium to the tube.Place the tube at a 45-degree position inside a cell culture incubator for one hour at 37 degrees Celsius. During the one-hour incubation, mix the solution every 15 minutes with a five-milliliter pipette. After incubation, add five milliliters of medium and mix well.Then, sort the solution with a 100-micrometer cell strainer using a sterile 50-milliliter tube. Centrifuge the sorted cells at 500g for 10 minutes at room temperature. Aspirate the supernatant and resuspend the pellet in three milliliters of 1x RBC Lysis Buffer solution.Incubate for 10 minutes at room temperature. Then, add three milliliters of medium and mix the sample. Centrifuge at 500g for 10 minutes at room temperature and aspirate the supernatant.Resuspend the pellet with five to 10 milliliters of medium, and use a cell counter to calculate the total number of cells. After centrifuging the cells at 500g for 10 minutes at room temperature, resuspend in 10 milliliters of PBS. Repeat the centrifugation and wash with 10 milliliters of PBS.Resuspend the pellet to obtain a concentration of 20 times 10 to the six cells per milliliter and mix well to obtain a homogeneous cell suspension. Next, prepare a 29g syringe for cecum injection. Load 50 microliters of the tumor cell suspension into the syringe, and ensure that no air bubbles remain in the syringe.Place the syringe on ice. First, sterilize the surgical site by spraying with disinfecting detergent and wiping. Then, depilate the abdomen using a mouse hair removal machine.Place the mouse in a supine position and disinfect the abdomen by scrubbing with chlorhexidine or povidone-iodine. Make a one-centimeter longitudinal incision over the lower abdomen using surgery scissors. Carefully separate the skin to the sides to expose the peritoneum.Then, make a 0.5 to one-centimeter incision in the peritoneum membrane, sufficient to exteriorize the cecum. Using a precut sterile gauze, carefully isolate the cecum from the mouse. Moisten the cecum was saline solution throughout the procedure.Immobilize the cecum by carefully holding it with forceps, then introduce the needle superficially into the cecum wall. Slowly, inject the entire 50 microliter volume of tumor cell suspension. This process takes around 10 seconds.After injection, slowly remove the needle from the cecum and apply gentle pressure on the injection site with a cotton tip applicator. Clean the cecum with saline solution to remove any debris and return the cecum back to the abdomen of the animal. Close the peritoneum using 5/0 sutures and then close the skin of the abdomen using 5/0 sutures.Orthotopic CRC-PDX tumors were observed in the intestine of mice implanted with patient-derived cancer cells. Histological analysis by hematoxylin and eosin staining on the cecum showed the presence of tumor cells. The histological analysis also revealed lung metastasis and liver metastasis in the implanted mice.Mice carrying orthotopic tumors were treated with either the vehicle, testing drug, or the chemotherapy drug irinotecan. Analysis of micro CT scanning images showed that compared to the vehicle, the testing drug induced a reduction of the tumor volume, which was further reduced in combination with irinotecan treatment. This model will help to study the biology of the metastasis in colorectal cancer tumors.

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