John:

If we examine the cumulative evidence to date using the various leading models of APC, AOM, MNU, BMBDD, MMR,TGF-b, xenograft, and the non-murine zebrafish, models of human colorectal cancer (CRC) disease, then the orthotopic model (especially orthotopic implantation) has the advantage of closely mimicking human CRC including tumor microenvironment [1,2,3,4;10]. It recapitulates all of the critical components of the tumor microenvironment, as well as all of the angiogenic factors, growth factors, and cytokines, thus finely mimicking the human CRC in terms of both metastasis and microenvironments, allowing evaluation of the alterations in and modulations of the microenvironment on tumorigenesis and progression [4].

Thus, Japanese investigators [8] evaluated the efficacy of anti-human VEGF antibody (bevacizumab) with or without irinotecan (CPT-11) postoperative adjuvant therapy against lung metastases in which neovascularization was already induced using orthotopically implanted colon cancer in rat, and the results from orthotopic-implantation tumor model suggested that a higher efficacy may be expected when bevacizumab is combined with the cytotoxic agent irinotecan (CPT-11), compared to bevacizumab monotherapy, and this has indeed been clinically confirmed [8]. In contrast, the xenograft model fails to represent the CRC tumor microenvironment, and with potential divergence of signaling pathways between its model and human disease [5,6,7].

These facts lead to a well-evidenced principle: that drugs that modulate the tumor microenvironment and the tumor-host interaction - as do so many oncologic agents - must be studied in orthotopic models [9], and recently these models have been extended and refined into sophisticated GEMM-derived orthotopic transplant models of Kras-mutant colorectal cancer for high-throughput drug discovery screening and candidate drug validation [11].

REFERENCES

1. Tseng, W.; Leong, X. & Engleman, E. (2007). Orthotopic mouse model of colorectal cancer. J Vis Exp, 484.

2. Pocard M, Tsukui H, Salmon RJ, Dutrillaux B, Poupon MF: Efficiency of orthotopic xenograft models for human colon cancers. In Vivo 1996; 10:463–469.

3. Wilmanns C, Fan D, O’Brian CA, Bucana CD, Fidler IJ: Orthotopic and ectopic organ environments differentially influence the sensitivity of murine colon carcinoma cells to doxorubicin and 5-fluorouracil. Int J Cancer 1992;52:98–104.

4. Suman S, Fornace AJ, Datta K. Animal Models of Colorectal Cancer in Chemoprevention and Therapeutics Development, Colorectal Cancer - From Prevention to Patient Care, 2012. Dr. Rajunor Ettarh (Ed.), ISBN: 978-953-51-0028-7, InTech.

5. Furukawa T, Kubota T, Watanabe M, et al. A metastatic model of human colon cancer constructed using cecal implantation of cancer tissue in nude mice. Surg Today, 1993; 23, 420-423. 2. Fidler, IJ. New developments in in vivo models of neoplasia. Cancer Metastasis 1991; Rev, 10, 191-192.

6. Fidler, IJ. Orthotopic implantation of human colon carcinomas into nude mice provides a valuable model for the biology and therapy of metastasis. Cancer Metastasis Rev 1991; 10, 229-243.

7. Fidler, IJ. (1991c). The biology of cancer metastasis or, 'you cannot fix it if you do not know how it works'. Bioessays 1991; 13, 551-554.

8. Mizobe, T.; Ogata, Y.; Murakami, H, et al. Efficacy of the combined use of bevacizumab and irinotecan as a postoperative adjuvant chemotherapy in colon carcinoma. Oncol Rep 2008; 20, 517-523.

9. Heijstek MW, Kranenburg O, Borel Rinkes IH. Mouse models of colorectal cancer and liver metastases. Dig Surg 2005; 22(1-2):16-25.

10. Rajput A, Agarwal E, Leiphrakpam P, Brattain MG, Chowdhury S.Establishment and Validation of an Orthotopic Metastatic Mouse Model of Colorectal Cancer. ISRN Hepatology 2013. Article ID 206875.

11. Martin ES, Belmont PJ, Sinnamon MJ, et al. Development of a colon cancer GEMM-derived orthotopic transplant model for drug discovery and validation. Clin Cancer Res 2013 Jun 1; 19(11):2929-40.

Thank you!