Elucidating the roles of retinoic acid and enteric glia in colorectal cancer
Abstract/Contents
- Abstract
- Colorectal cancer (CRC) is the third most commonly diagnosed cancer and third leading cause of cancer mortality in the United States, highlighting an urgent need for greater understanding of the mechanisms underpinning CRC development. Here, we find that mice with colitis-associated CRC exhibit a marked decrease in colonic all-trans retinoic acid (atRA) due to alterations in the atRA metabolic enzymes. Patients with ulcerative colitis (UC), UC-associated CRC, and sporadic CRC additionally exhibit similar alterations, consistent with reduced colonic atRA. In mice, inhibition of atRA signaling promoted tumorigenesis, whereas supplementation of atRA reduced tumor burden. This anti-tumor effect was mediated by CD8+ T cells, which were activated as a result of MHC I upregulation on the tumor epithelial cells. Consistent with these findings, increased colonic expression of the atRA catabolizing enzyme, CYP26A1, in CRC patients was found to correlate with reduced frequencies of tumoral cytotoxic CD8+ T cells and with worse disease prognosis. Additionally, we also discovered that enteric glial cells play a critical role in early CRC development. Although the mechanism remains elusive, we demonstrate that the pro-tumorigenic function of the glia does not depend on effects on CD8+ T cells or intestinal inflammation. Altogether, our work here reveals two heretofore undescribed mechanisms of CRC tumor development and identifies potential new targets for prevention and treatment of CRC.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2018; ©2018 |
| Publication date | 2018; 2018 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Yuan, Robert |
|---|---|
| Degree supervisor | Engleman, Edgar G |
| Thesis advisor | Engleman, Edgar G |
| Thesis advisor | Butcher, Eugene |
| Thesis advisor | Habtezion, Aida |
| Thesis advisor | Negrin, Robert S |
| Degree committee member | Butcher, Eugene |
| Degree committee member | Habtezion, Aida |
| Degree committee member | Negrin, Robert S |
| Associated with | Stanford University, Department of Immunology. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Robert Yuan. |
|---|---|
| Note | Submitted to the Department of Immunology. |
| Thesis | Thesis Ph.D. Stanford University 2018. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2018 by Robert Yuan
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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