Abstract
Purpose
Realistic models of colorectal cancer are necessary to study cancer biology and evaluate therapeutic interventions. Real-time observation and repeated sampling of implanted tumor is difficult to achieve in the current orthotopic animal colorectal cancer model. The aim of this study was to establish a simple colostomy implantation mouse model for evaluating colon cancer.
Experimental design
The human colon cancer cell line LoVo was injected subcutaneously into the necks of five mice to generate a solid tumor. Colostomies were created from the ceca of 14 nude mice. Fragments from the solid tumors were then harvested and implanted into the submucosa of the stoma. Half of the tumor-bearing mice were treated with 5-fluorouracil (5-FU) and all were monitored for tumor growth and survival. Tumor tissue was taken at different time points to evaluate pathological changes, expression of hMSH2 and P53, and microsatellite instability (MSI).
Results
The stoma healed 2 weeks after the surgery. Twelve mice had developed detectable colon tumor 2 to 3 weeks after implantation of human colon cancer LoVo cells into the colostomy with mesenteric lymph node metastases. The median survival was 13 weeks. Histopathological and immunohistochemical examinations of tumor tissues collected at different time points of tumor progression showed similar histopathological changes and hMSH2 and P53 expression patterns to the original cell line. MSI analysis showed that five tumors were MSI-L from the second week after tumor implantation and all 12 colostomy tumors were MSI-H from 4 weeks after implantation. The tumors were highly sensitive to 5-FU treatment, which lead to a longer median survival of 15 weeks (P = 0.0374) and significant tumor growth inhibition.
Conclusion
This study demonstrates that a colostomy implantation mouse model is an ideal model for evaluating colon cancer. Its advantages include high tumor take rate, easy real-time visualization, easy repeated sampling of the implanted tumor in live animals, and significant sensitivity to a commonly used chemotherapeutic agent.
Similar content being viewed by others
References
Taketo MM (2006) Mouse models of gastrointestinal tumors. Cancer Sci 97(5):355–361
Hata K, Tanaka T, Kohno H, Suzuki R, Qiang SH, Yamada Y, Oyama T, Kuno T, Hirose Y, Hara A, Mori H (2006) Beta-catenin-accumulated crypts in the colonic mucosa of juvenile ApcMin/+ mice. Cancer Lett 239(1):123–128
Sodir NM, Chen X, Park R, Nickel AE, Conti PS, Moats R, Bading JR, Shibata D, Laird PW (2006) Smad3 deficiency promotes tumorigenesis in the distal colon of ApcMin/+ mice. Cancer Res 66(17):8430–8438
Tokairin Y, Kakinuma S, Arai M, Nishimura M, Okamoto M, Ito E, Akashi M, Miki Y, Kawano T, Iwai T, Shimada Y (2006) Accelerated growth of intestinal tumours after radiation exposure in Mlh1-knockout mice: evaluation of the late effect of radiation on a mouse model of HNPCC. Int J Exp Pathol 87(2):89–99
Leclerc D, Deng L, Trasler J, Rozen R (2004) ApcMin/+ mouse model of colon cancer: gene expression profiling in tumors. J Cell Biochem 93(6):1242–1254
Pocard M, Tsukui H, Salmon RJ, Dutrillaux B, Poupon MF (1996) Efficiency of orthotopic xenograft models for human colon cancers. In Vivo 10(5):463–469
Hoffman RM (1994) Orthotopic is orthodox. Why are orthotopic-transplant metastatic models different from all other models? J Cell Biochem 56:1–3
Rashidi B, Sun FX, Jiang P, An Z, Gamagami R, Moossa AR, Hoffman RM (2000) A nude mouse model of massive liver and lymph node metastasis of human colon cancer. Anticancer Res 20(2A):715–722
Kashtan H, Rabau M, Mullen JB, Wong AH, Roder JC, Shpitz B, Stern HS, Gallinger S (1992) Intra-rectal injection of tumor cell: a novel animal model of rectal cancer. Surg Oncol 1(3):251–256
Chen Y, Chang KJ, Hwang LH, Chen CN, Tseng SH (2002) Establishment and characterization of a rectal cancer model in mice: application to cytokine gene therapy. Int J Colorectal Dis 17:388–395
Berg KD, Glaser CL, Thompson RE, Hamilton SR, Griffin CA, Eshleman JR (2000) Detection of microsatellite instability by fluorescence multiplex polymerase chain reaction. J Mol Diagnostics 2:20–28
Umar A, Boland CR, Terdiman JP (2004) Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:261–268
Rüschoff J, Wallinger S, Dietmaier W, Bocker T, Brockhoff G, Hofstädter F, Fishel R (1998) Aspirin suppresses the mutator phenotype associated with hereditary nonpolyposis colorectal cancer by genetic selection. Genetics 95:11301–11306
Wang X, Fu X, Hoffman RM (1992) A new patient-like metastatic model of human lung cancer constructed orthotopically with intact tissue via thoracotomy in immunodeficient mice. Int J Cancer 51:992–995
Fu X, Besterman JM, Monosov A, Hoffman RM (1991) Models of human metastatic colon cancer in nude mice orthotopically constructed by using histologically-intact patient specimens. Proc Natl Acad Sci USA 88:9345–9349
Marchal F, Tran N, Marchal S, Leroux A, Marchal C, Bolotine L, Guillemin F, Villemot JP (2005) Development of an HT29 liver metastases model in nude rats. Oncol Rep 14(5):1203–1207
Flatmark K, Maelandsmo GM, Martinsen M, Rasmussen H, Fodstad O (2004) Twelve colorectal cancer cell lines exhibit highly variable growth and metastatic capacities in an orthotopic model in nude mice. Eur J Cancer 40:1593–1598
Acknowledgement
The study was funded by the National Natural Science Foundation of China (2005).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Jin, H., Liu, X., Li, V.k.m. et al. A simple colostomy implantation model for evaluating colon cancer. Int J Colorectal Dis 24, 41–47 (2009). https://doi.org/10.1007/s00384-008-0569-y
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00384-008-0569-y