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Published on: October 6, 2014
Compound disruption of smad2 accelerates malignant progression of intestinal tumors in apc knockout mice
Toshiaki Hamamoto1, Hideyuki Beppu, Hitoshi Okada
1Departments of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo 170-8455, Japan.
Abstract:
Smad2 is a receptor-regulated Smad that is activated specifically by transforming growth factor beta and activin signaling. We disrupted the mouse Smad2 gene by gene targeting. Homozygous Smad2 mutant mice died around E8.5 with impaired visceral endoderm function and deficiency of mesoderm formation. Heterozygotes were fertile and had no apparent abnormality up to at least 1 1/2 year of age. To examine the role of Smad2 inactivation in the process of carcinogenesis, we prepared compound heterozygous mice, which carry both Apc and Smad2 mutations on the same chromosome in the cis-configuration. Compound inactivation of Smad2 in heterozygous Apc mutant mice did not change the total number of intestinal tumors but increased sudden death from intestinal obstruction caused by extremely large tumors. Furthermore, histological examination revealed that Apc/Smad2 cis-compound heterozygotes developed multiple invasive cancers that had never been observed in Apc single heterozygotes. These results indicate that loss of Smad2 does not initiate tumorigenesis by itself but accelerates malignant progression of tumors to invasive cancer in the late stages of carcinogenesis.
Insights
Loss of Smad2 in mice impairs early development but does not initiate cancer. However, Smad2 deficiency accelerates tumor progression to invasive cancer in Apc mutant mice.
Area of Science:
- Developmental Biology
- Cancer Biology
- Genetics
Background:
- Smad2 is a key mediator in transforming growth factor beta (TGF-β) and activin signaling pathways.
- These pathways are crucial for embryonic development and cellular homeostasis.
Purpose of the Study:
- To investigate the role of Smad2 in early embryonic development.
- To determine the effect of Smad2 inactivation on intestinal tumorigenesis and cancer progression.
Main Methods:
- Gene targeting was used to disrupt the mouse Smad2 gene.
- Compound heterozygous mice carrying Apc and Smad2 mutations were generated and analyzed.
- Histological examination of intestinal tumors was performed.
Main Results:
- Smad2 homozygous mutant mice exhibited embryonic lethality around E8.5 due to impaired visceral endoderm function and mesoderm deficiency.
- Apc/Smad2 compound heterozygotes showed no change in tumor number but increased mortality from intestinal obstruction.
- Histological analysis revealed the development of multiple invasive cancers in Apc/Smad2 compound heterozygotes, unlike in Apc single heterozygotes.
Conclusions:
- Smad2 is essential for normal embryonic development.
- Loss of Smad2 does not initiate tumorigenesis but significantly accelerates the malignant progression of existing tumors to invasive cancer in a mouse model.
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