Related Experiment Videos
Decreased transforming growth factor beta type II receptor expression in intestinal adenomas from Min/+ mice is
T Zhang1, L B Nanney, M O Peeler
1Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Abstract:
Tumor cells often become resistant to the growth-inhibitory effects of transforming growth factor beta (TGF-beta). Recent studies have identified TGF-beta type II receptor (RII) mutations in a subset of cancers, including colon cancer. To evaluate the expression of TGF-beta RII in premalignant intestinal adenomas and the relationship with cell cycle regulation, we investigated the expression of TGF-beta RII, cyclin D1, and cyclin-dependent kinase 4 (Cdk4) in Min/+ mouse intestinal adenomas. Immunohistochemistry indicated that TGF-beta RII cytoplasmic immunoreactivity was undetectable in the proliferative crypt zones of the normal small intestinal and normal colonic epithelium but was abundant toward the villus tips of the normal small intestine and the lumenal third of the colonic glands. As was observed in the proliferating crypt zones, TGF-beta RII immunoreactivity was dramatically decreased or undetectable in all adenomas examined in comparison to the abundant levels in adjacent normal differentiated intestinal epithelium. TGF-beta RII mRNA was also reduced in the adenomas in comparison to normal mucosa as determined by reverse transcription-PCR. In an inverse distribution to TGF-beta RII, Cdk4 nuclear immunoreactivity was restricted to the crypt regions of the small and large intestine, whereas cyclin D1 immunoreactivity was uniformly absent in normal intestinal epithelium. For both cyclin D1 and Cdk4, protein and mRNA levels were increased in intestinal adenomas but not in normal intestinal epithelium as determined by immunohistochemistry, in situ hybridization, and reverse transcription-PCR. In summary, the lack of TGF-beta RII expression was associated with increased cyclin D1 and Cdk4 expression in Min/+ mouse intestinal adenomas. We hypothesize that the former may enable tumor cells to escape from the normal growth-constraining influence of TGF-beta, whereas the latter promotes inappropriate cell proliferation and adenoma progression.
Insights
Loss of transforming growth factor beta type II receptor (TGF-beta RII) expression in mouse intestinal adenomas correlates with increased cyclin D1 and Cdk4. This suggests TGF-beta RII loss promotes tumor growth by escaping growth inhibition and enhancing proliferation.
Area of Science:
- Oncology
- Molecular Biology
- Gastroenterology
Background:
- Tumor cells frequently develop resistance to the growth-inhibitory effects of transforming growth factor beta (TGF-beta).
- Mutations in the TGF-beta type II receptor (RII) have been identified in various cancers, including colon cancer.
Purpose of the Study:
- To investigate the expression of TGF-beta RII in premalignant intestinal adenomas.
- To determine the relationship between TGF-beta RII expression and cell cycle regulators (cyclin D1, Cdk4) in intestinal adenomas.
Main Methods:
- Immunohistochemistry to assess protein expression of TGF-beta RII, cyclin D1, and Cdk4.
- Reverse transcription-polymerase chain reaction (RT-PCR) to evaluate mRNA levels.
- In situ hybridization for cyclin D1 and Cdk4 mRNA detection.
Main Results:
- TGF-beta RII immunoreactivity was significantly decreased or absent in intestinal adenomas compared to normal differentiated intestinal epithelium.
- TGF-beta RII mRNA levels were also reduced in adenomas.
- Cyclin D1 and Cdk4 expression (protein and mRNA) were elevated in intestinal adenomas, with an inverse distribution to TGF-beta RII.
Conclusions:
- Loss of TGF-beta RII expression in intestinal adenomas is associated with increased expression of cyclin D1 and Cdk4.
- This downregulation of TGF-beta RII may allow tumor cells to evade TGF-beta-mediated growth suppression.
- Elevated cyclin D1 and Cdk4 likely contribute to uncontrolled cell proliferation and adenoma progression.