Smad7 and Colorectal Carcinogenesis: A Double-Edged Sword
Edoardo Troncone1, Giovanni Monteleone2
1Department of Systems Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy. troncone.edoardo@gmail.com.
Abstract:
Colorectal carcinogenesis is a complex process in which many immune and non-immune cells and a huge number of mediators are involved. Among these latter factors, Smad7, an inhibitor of the transforming growth factor (TGF)-β1 signaling that has been involved in the amplification of the inflammatory process sustaining chronic intestinal inflammation, is supposed to make a valid contribution to the growth and survival of colorectal cancer (CRC) cells. Smad7 is over-expressed by tumoral cells in both sporadic CRC and colitis-associated CRC, where it sustains neoplastic processes through activation of either TGFβ-dependent or non-dependent pathways. Consistently, genome-wide association studies have identified single nucleotide polymorphisms of the Smad7 gene associated with CRC and shown that either amplification or deletion of the Smad7 gene associates with a poor prognosis or better outcome, respectively. On the other hand, there is evidence that over-expression of Smad7 in immune cells infiltrating the inflamed gut of patients with inflammatory bowel disease can elicit anti-tumor responses, with the down-stream effect of attenuating CRC cell growth. Taken together, these observations suggest a double role of Smad7 in colorectal carcinogenesis, which probably depends on the cell subset and the biological context analyzed. In this review, we summarize the available evidences about the role of Smad7 in both sporadic and colitis-associated CRC.
Insights
Smad7, a transforming growth factor-beta inhibitor, plays a dual role in colorectal cancer (CRC) development. Its overexpression in tumor cells promotes CRC, while in immune cells, it may offer anti-tumor effects.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Colorectal carcinogenesis involves complex interactions between immune and non-immune cells.
- Transforming growth factor-beta (TGF-β) signaling and its inhibitor, Smad7, are implicated in chronic intestinal inflammation and colorectal cancer (CRC) progression.
Purpose of the Study:
- To review the multifaceted role of Smad7 in both sporadic and colitis-associated colorectal cancer.
- To elucidate the dual function of Smad7 in CRC, considering its expression in different cell types and biological contexts.
Main Methods:
- Review of existing literature on Smad7's involvement in colorectal carcinogenesis.
- Analysis of studies examining Smad7 expression in tumor cells and infiltrating immune cells in CRC patients.
- Examination of genetic evidence, including single nucleotide polymorphisms and gene copy number variations of Smad7 in relation to CRC.
Main Results:
- Smad7 is overexpressed in tumor cells in both sporadic and colitis-associated CRC, promoting cancer growth via TGF-β-dependent and independent pathways.
- Genetic variations in Smad7 are associated with CRC risk, with gene amplification linked to poor prognosis and deletion to better outcomes.
- Overexpression of Smad7 in immune cells within inflamed gut tissues may exert anti-tumor effects, reducing CRC cell growth.
Conclusions:
- Smad7 exhibits a context-dependent, dual role in colorectal carcinogenesis.
- Its function in CRC progression is influenced by the specific cell type (tumor vs. immune) and the overall biological environment.
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