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Longitudinal Assessment of Colonic Tumor Fate in Mice by Computed Tomography a nd Optical Colonoscopy

Posted Nov 30, 2009 Updated Apr 7, 2023
By Benjamin Y. Durkee PhD , Kazuhiko Shinki PhD , Michael A. Newton PhD , Caitlin E. Iverson BS , Jamey P. Weichert PhD , William F. Dove PhD , Richard B. Halberg PhD
9 min read

Rationale and Objectives

The purpose of this study was to evaluate the relative merits of micro-computed tomograph colonography (mCTC) and optical colonoscopy (OC) for longitudinal studies of colonic tumors in mice.

Materials and Methods

Colonic tumors in mice carrying the Min allele of Apc were followed over several weeks using mCTC and OC. A total of 146 colonic tumors were monitored: 62 in 32 untreated Min mice, 53 in 43 Min mice treated with 5-fluorouracil (5-FU), and 31 in 17 Min mice treated with piroxicam.

Results

Colonic tumors in Min mice had three different spontaneous fates: 29 grew, 24 remained static, and 9 regressed. Treating Min mice with 5-FU increased the percentage of regressing tumors from 15% to 58%. The response was dependent in part on the initial size of the tumor. By contrast, treating Min mice with piroxicam did not alter colonic tumor fate.

Conclusions

mCTC and OC can be used to determine the spontaneous fates of colonic tumors in mice and to document their individual responses to treatment. The ability to follow individually annotated colonic tumors reduces the number of mice needed for testing.

Murine models of human colorectal cancer afford investigators the opportunity to rapidly test newly developed treatments. The Apc Min/+ (Min) mouse carries a nonsense mutation in codon 850 of the Adenomatous polyposis coli ( Apc ) gene and develops benign adenomas along the entire length of the intestinal tract . This model has been used over the past 18 years to test at least 269 treatments, including dietary supplements, nonsteroidal anti-inflammatory drugs, and exercise . For example, Jacoby et al exposed 15 Min mice to 100 ppm piroxicam via the diet for 42 days . Tumor multiplicity in a 4-cm segment of the distal small intestine was reduced from 10 ± 2 to 2 ± 1. This protective effect of piroxicam in the small intestine has been confirmed in several independent studies .

A limitation of genetic mouse models for human colon cancer is that tumors develop primarily in the small intestine instead of the colon . The low multiplicity of colonic tumors leads to the need for large experimental cohorts of mice for statistical significance in studies with a traditional cross-sectional design. This limitation can be overcome by longitudinally monitoring individually annotated colonic tumors in mice, where the statistical power depends on the ability to monitor the tumor response rather than on tumor multiplicity. In vivo imaging modalities such as magnetic resonance imaging (MRI), micro-computed tomograph colonography (mCTC), and optical colonoscopy (OC) may provide complementary tools to monitor longitudinally the biology and therapeutics of colonic tumors .

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Methods

Mice

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Treatment with 5-FU or Piroxicam

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Figure 1, The experimental designs of the longitudinal studies are represented schematically with the number of mice, the number of tumors, and tumor fates shown for all groups of mice.

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Figure 2, The fates of colonic tumors in Min mice were assessed noninvasively by micro-computed tomography. Min controls were scanned at least three separate times between 50 and 105 days of age. (a) The volume of each individually annotated tumor was estimated from images collected during a visit (volume of tumor indicated by arrow = 9.73 mm 3 ). (b) Colonic tumors in Min mice exhibit three different spontaneous fates: growth, stasis, and regression.

Figure 3, Tumor fate is affected by a single cycle of 5-fluorouracil (5-FU) or multiple cycles of 5-FU, but not piroxicam. Mice were scanned before treatment (Day 0) and immediately prior to sacrifice. Tumor fate following treatment with 5-FU was affected by initial volume: <5 mm 3 (left) and >5 mm 3 (right) . Regression (dotted lines) and growth (solid lines) are defined by a 16% (95% confidence level) or more decrease or increase in tumor volume, respectively. In the panel for controls with initial volume >5 mm 3 , two of the lines for regressing tumors overlap; there were four regressing tumors in this set.

Figure 4, The fates of colonic tumors in Min mice were assessed by OC. (a) A tumor in an untreated mouse grew significantly in 3 weeks. (b) A large colonic tumor (white arrow) regressed dramatically following a single cycle of 5-fluorouracil (5-FU) treatment, but a smaller one (black arrow) did not. Another regressing tumor had an opaque mass at the center of the lesion (red arrow) . (c) A colonic tumor did not respond to a 3-week treatment with piroxicam.

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MicroCT Colonography

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Multiple Regression Analysis

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Optical Colonoscopy (OC)

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Treatment with Dextran Sodium Sulfate (DSS) Plus Piroxicam

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Power

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Results

The Range of Tumor Fates in Control Mice

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Response of Colonic Tumors to 5-FU

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Table 1

Several Factors Affect Tumor Volume in Treated Mice and Controls

95% Confidence Interval Factor ∗ Mean Effect † Standard Error Lower Upper_P_ Value Initial volume ‡ -0.042 0.017 -0.080 -0.017 .014 Sex § 0.199 0.075 0.041 0.343 .008 5-FU -0.335 0.092 -0.531 -0.170 .001 Age 0.002 0.003 -0.004 0.007 .502 Body mass -0.062 0.040 -0.143 0.016 .121

5-FU, 5-fluorouracil.

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Resistance of Colonic Tumors to Piroxicam

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DSS-piroxicam Treatment of Min Mice Alters Tumor Distribution and Leads to Enhanced Longevity

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Discussion

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Acknowledgments

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Academic Radiology, Volume 16, Issue 12
Journals General Radiology
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