A novel mouse model for segmental orthotopic colon cancer

Abstract

Spontaneous colon tumor mouse strains offer numerous advantages in modeling disease. However, the wide temporal window in which lesions form and the stochastic nature of lesion location require larger cohorts for assessment of disease modulation. Reliable, reproducible and inexpensive mouse models of early-stage and invasive cancer would add to existing transgenic models. We show a new method for the creation of orthotopic murine tumors centered in the mucosal and submucosal layers anywhere in the colon, allowing creation of lesions of known age, location and extent. The system overcomes the disadvantages of heterotopic implantation and allows evaluation of lesions distally in the colon as well as proximally, thereby providing an additional method to study the effects of regionality. Invasion, host vascularization and application to disparate cell lines are demonstrated. Noninvasive imaging with magnetic resonance and colonoscopy, allowed in part by the tumor location, show potential applications of this approach. ' 2005 Wiley-Liss, Inc.Key words: colon cancer; mouse model; colonoscopy; magnetic resonance imaging A number of spontaneous colorectal tumor mouse strains have been developed that model human cancer syndromes, such as HNPCC, 1 and familial adenomatous polyposis. 2-5 These mouse models, which allow monitoring of the phenotypic effects of known genetic alterations, have proved invaluable in understanding disease course and evaluating novel therapies. 6 The typically slower growth rates in the resulting spontaneous tumors compared to implanted cell lines more closely emulate the rates of human tumor growth. However, many of the most-used mouse models form adenomas primarily in the small bowel, with relatively few lesions in the descending and sigmoid colon. Noninvasive serial imaging of small bowel lesions to evaluate anatomic size changes is quite challenging in humans and markedly more difficult in mice. Additionally, few transgenic models of invasive colorectal cancer exist; 7 the commonly used Apc Min1/2 mice typically develop adenomas but not invasive adenocarcinomas.A disadvantage for the use of these models to evaluate therapeutics is that the broad temporal variability in lesion formation and the difficulty in nondestructive serial evaluation require very large cohorts of animals to be examined over extended periods of time to realize efficacy of treatment, with mortality often used as an end point. Alternatively, heterotopic s.c. implantation of tumor cell lines suffers from incongruent host stroma, which has been shown to change tumorigenicity 8 and cell cycle regulation 9 for implanted tumors compared to implantation in the native tissue bed. Additionally, direct injection of tumor cells into murine colonic mucosa or submucosa is technically difficult and has not been reported. We hypothesized that orthotopic implantation could be achieved with focal enzymatic disruption of the colonic mucosal layer only and placement of tumor cells intraluminally. The resulting tumors ''arise'' from the muco...

Enhanced progression of human prostate cancer PC3 cells induced by the microenvironment of the seminal vesicle

“…*, differs from control (Po0.01). (Gohji et al, 1997;Sato et al, 1997;Alencar et al, 2005). In this study as well, lymph node metastases was observed in some mice following injection of PC3 cells into the prostate as described previously (Saffran et al, 2001); however, disease progression in mice following the SV injection of PC3 cells was more prominent than that in mice following intraprostatic injection.…”

“…To date, a number of studies have demonstrated a significant impact of organ microenvironment on disease progression of various types of human malignant tumours (Gohji et al, 1997;Sato et al, 1997;Alencar et al, 2005); however, there have not been any studies investigating the significance of the SV microenvironment as a factor influencing the progression of prostate cancer. In this study, therefore, we focused on the role of microenvironment of the SV, and evaluated its effects on changes in malignant phenotypes of human prostate cancer PC3 cells both in vitro and in vivo.…”

“…A number of studies have demonstrated significant effects of organ microenvironment on the malignant potentials in several types of cancer cells, including prostate cancer, using in vivo experimental models (Gohji et al, 1997;Sato et al, 1997;Alencar et al, 2005). For example, Gohji et al reported that human renal cancer cells implanted in the subcutis of nude mice produced local nonmetastatic tumours, whereas the same cells orthotopically implanted in the kidney resulted in the formation of local tumours and metastases to the lungs.…”

N-Cadherin and Keratinocyte Growth Factor Receptor Mediate the Functional Interplay between Ki-RASG12V and p53V143A in Promoting Pancreatic Cell Migration, Invasion, and Tissue Architecture Disruption

“…6), which was confirmed by MR imaging (Fig. 6), a powerful, high-resolution imaging modality (4,12). The bioluminescence measurements revealed focal activities and were done with animals imaged using a left anterior oblique view to optimize imaging of the pancreatic tail.…”

A GFP-labeled Human Colon Cancer Metastasis Model Featuring Surgical Orthotopic Implantation

“…However, the gene knock-out and chemically induced model typically undergo substantial changes during the development of mice tumors and it is difficult to make non-invasive (Alencar et al, 2005). Whereas the subcutaneous tumor model is easy to establish and convenient for observation, due to the fact that the tumor cells grow in abnormal host environment, the biological properties of the tumor changed notably (Carlomagno et al, 2006;Teicher et al, 2006).…”