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Updated: Aug 12, 2026
Modeling Colitis-Associated Cancer with Azoxymethane (AOM) and Dextran Sulfate Sodium (DSS)
Published on: September 11, 2012
Aberrant transforming growth factor-beta signaling in azoxymethane-induced mouse colon tumors
K Guda1, C Giardina, P Nambiar
1Center for Molecular Medicine, University of Connecticut Health Center, Farmington, CT 06030-3101, USA.
Abstract:
Alterations in the transforming growth factor-beta (TGF-beta) pathway are implicated in the pathogenesis of colorectal cancer. We hypothesize that alterations in the TGF-beta pathway contribute to differential sensitivity of mice to the colon carcinogen azoxymethane (AOM). A/J (sensitive) and AKR/J (resistant) mice were injected intraperitoneally with AOM (10 mg/kg of body weight once a week for 6 wk). Twenty-four weeks after AOM exposure, mutational analysis of TGF-beta type II receptor (TbetaR-II) from normal colons and from tumors showed no AOM-induced alterations. A significant decrease (1.5-fold, P < 0.05) in TbetaR-II mRNA levels, however, was found in A/J tumors with the RNase protection assay. Immunofluorescence of TbetaR-II showed marked loss of staining in A/J tumors. The RNase protection assay and sequence analysis of the downstream signaling molecule Smad3 revealed no carcinogen-induced alterations in either strain. To gain further insight into the functionality of the pathway, expression of TGF-beta, TGF-beta type I receptor (TbetaR-I), and several downstream targets of TGF-beta signaling, including Smad7, c-myc, and p15, was examined. Although no alterations in TGF-beta, TbetaR-I, or Smad7 were found in tumors, a significant increase in c-myc expression (2.5-fold, P < 0.05 ) and a significant decrease in p15 expression (4.5-fold, P < 0.05 ) were noted. Concomitant repression of TbetaR-II and overexpression of c-myc may render epithelial cells insensitive to TGF-beta-mediated growth arrest, a possibility that also is suggested by this model. The significant decrease in p15 expression in tumors provides additional evidence that TGF-beta signaling may be markedly attenuated during colon tumorigenesis.
Insights
Transforming growth factor-beta (TGF-beta) pathway alterations impact colorectal cancer. This study found reduced TGF-beta type II receptor (TbetaR-II) in sensitive mice, suggesting pathway attenuation contributes to colon tumorigenesis.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Transforming growth factor-beta (TGF-beta) signaling is crucial in cellular processes and its dysregulation is linked to colorectal cancer pathogenesis.
- Genetic and molecular alterations in the TGF-beta pathway are implicated in cancer development, affecting cell growth, differentiation, and apoptosis.
Purpose of the Study:
- To investigate the role of TGF-beta pathway alterations in differential sensitivity of A/J (sensitive) and AKR/J (resistant) mice to azoxymethane (AOM)-induced colon cancer.
- To determine if AOM exposure induces mutations or changes in TGF-beta pathway components, including TbetaR-II, Smad3, and downstream targets.
Main Methods:
- Mice (A/J and AKR/J) were exposed to azoxymethane (AOM), a colon carcinogen.
- Analysis of TGF-beta type II receptor (TbetaR-II) mutations, mRNA levels, and protein expression in normal colons and tumors.
- Assessment of downstream signaling molecules Smad3, Smad7, c-myc, and p15 expression using RNase protection assays and sequence analysis.
Main Results:
- No AOM-induced mutations in TbetaR-II were observed in either mouse strain.
- A significant decrease in TbetaR-II mRNA and protein levels was found in tumors from A/J mice.
- Increased c-myc and decreased p15 expression were noted in tumors, suggesting impaired TGF-beta signaling.
- No significant alterations in Smad3 or Smad7 were detected in response to AOM.
Conclusions:
- Reduced TbetaR-II expression and altered downstream targets (c-myc, p15) indicate significant attenuation of TGF-beta signaling in AOM-induced colon tumors.
- This pathway attenuation may contribute to the insensitivity of epithelial cells to TGF-beta-mediated growth arrest, promoting colon tumorigenesis.
- The study provides a model for understanding TGF-beta pathway involvement in colon cancer development and differential carcinogen sensitivity.
