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Published on: April 21, 2015
SMAD4 Suppresses Colitis-associated Carcinoma Through Inhibition of CCL20/CCR6-mediated Inflammation
David N Hanna1, Paula Marincola Smith2, Sergey V Novitskiy3
1Department of Surgery, Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee.
Background & Aims:
We previously reported that colon epithelial cell silencing of Smad4 increased epithelial expression of inflammatory genes, including the chemokine c-c motif chemokine ligand 20 (CCL20), and increased susceptibility to colitis-associated cancer. Here, we examine the role of the chemokine/receptor pair CCL20/c-c motif chemokine receptor 6 (CCR6) in mediating colitis-associated colon carcinogenesis induced by SMAD4 loss.
Methods:
In silico analysis of SMAD4, CCL20, and CCR6 messenger RNA expression was performed on published transcriptomic data from human ulcerative colitis (UC), and colon and rectal cancer samples. Immunohistochemistry for CCL20 and CCR6 was performed on human tissue microarrays comprising human UC-associated cancer specimens, Mice with conditional, epithelial-specific Smad4 loss with and without germline deletion of the Ccr6 gene were subjected to colitis and followed for up to 3 months. Tumors were quantified histologically, and immune cell populations were analyzed by flow cytometry and immunostaining.
Results:
In human UC-associated cancers, loss of epithelial SMAD4 was associated with increased CCL20 expression and CCR6+ cells. SMAD4 loss in mouse colon epithelium led to enlarged gut-associated lymphoid tissues and recruitment of immune cells to the mouse colon epithelium and stroma, particularly T regulatory, Th17, and dendritic cells. Loss of CCR6 abrogated these immune responses and significantly reduced the incidence of colitis-associated tumors observed with loss of SMAD4 alone.
Conclusions:
Regulation of mucosal inflammation is central to SMAD4 tumor suppressor function in the colon. A key downstream node in this regulation is suppression of epithelial CCL20 signaling to CCR6 in immune cells. Loss of SMAD4 in the colon epithelium increases CCL20 expression and chemoattraction of CCR6+ immune cells, contributing to greater susceptibility to colon cancer.
Insights
Loss of SMAD4 in colon cells increases inflammation and cancer risk by promoting CCL20/CCR6 signaling. Blocking this pathway reduces colitis-associated colon cancer in mice.
Area of Science:
- Gastroenterology
- Oncology
- Immunology
Background:
- SMAD4 loss in colon epithelial cells elevates inflammatory gene expression, including CCL20.
- This increases susceptibility to colitis-associated cancer.
- The role of the CCL20/CCR6 axis in SMAD4-loss-induced colon carcinogenesis is investigated.
Purpose of the Study:
- To examine the role of the chemokine/receptor pair CCL20/CCR6 in mediating colitis-associated colon carcinogenesis induced by SMAD4 loss.
Main Methods:
- In silico analysis of SMAD4, CCL20, and CCR6 mRNA in human UC and cancer samples.
- Immunohistochemistry for CCL20 and CCR6 in human UC-associated cancer specimens.
- Colitis induction in mice with conditional, epithelial-specific Smad4 loss, with and without Ccr6 gene deletion, followed by tumor quantification and immune cell analysis.
Main Results:
- Human UC-associated cancers with SMAD4 loss showed increased CCL20 and CCR6+ cells.
- SMAD4 loss in mice increased immune cell recruitment (T regulatory, Th17, dendritic cells) to the colon.
- CCR6 deletion abrogated these immune responses and significantly reduced colitis-associated tumor incidence.
Conclusions:
- SMAD4 tumor suppressor function in the colon involves regulating mucosal inflammation.
- Suppression of epithelial CCL20 signaling to CCR6 on immune cells is a key mechanism.
- Loss of SMAD4 promotes colon cancer by increasing CCL20 expression and CCR6+ immune cell chemoattraction.
