Abstract 4597: The G protein-coupled P2Y6 pyrimidoceptor protects colorectal cancerous epithelial cells from apoptosis: Is this receptor a novel target against colorectal cancer
Bibliographic record
Abstract
Abstract BACKGROUND. Colorectal cancer (CRC) originates from the accumulation of genetic mutations and epigenetic deregulation of tumor suppressor genes (TSGs) and oncogenes, most prominently APC, K-RAS, and TP53. As a result, transformed intestinal epithelial cells (IECs) acquire an evolutionary growth advantage leading to tumor formation. Like other solid tumors, various types of immune cells, and immunomodulatory molecules, including extracellular nucleotides, such as adenosine 5’-triphosphate (ATP) and uridine 5’-diphosphate (UDP), are found in the vicinity of colorectal tumors and promote tumor formation. In this context, activation of the G protein-coupled P2Y6 receptor (P2Y6R) by UDP could contribute to the formation of tumor-promoting microenvironment by modulating the immune response, as we previously reported, but also by coordinating resistance to apoptosis, one of the hallmarks of human CRC. METHODS: Colorectal cancer was induced in P2ry6 gene knockout mice (P2Y6−/−) using azoxymethane along with dextran sulfate sodium challenges. Mice were euthanatized and the number and size of tumor measured. Tissues were fixed and stained prior to histological characterization by a pathologist. In vitro, receptor expression level was determined by qPCR analysis in normal and cancerous IECs as well as from CRC tumor biopsies. Cell growth curves and clonogenic soft agar assays were realized to determine the effect of P2Y6R stimulation on cell growth and tumorigenic potential. Finally, the impact of P2Y6R activation on apoptosis was determined by analyzing apoptosis markers by western blotting. RESULTS: Invalidation of the P2ry6 gene in mice lead to a reduction in the number and size of colorectal tumors, which correlated with the ability of the activated P2Y6R to induce cancerous cell growth in both classical cell growth assays and clonogenic soft agar experiments. Furthermore, P2Y6R stimulation with UDP is not only stimulating cell growth but it also protects colorectal cancerous epithelial cells from TNF-induced apoptosis by a molecular mechanism involving the increase expression of the X-linked inhibitor of apoptosis protein (XIAP). CONCLUSIONS: In this study, we have shown that sustained activation of P2Y6R could contribute to intestinal tumorigenesis by blocking the apoptotic process and by stimulating cell growth. These results suggest that P2Y6R could be a prime target to reduce colorectal carcinogenesis. Citation Format: Morgane Placet, Caroline M. Molle, Guillaume Arguin, Sameh Geha, Fernand-Pierre Gendron. The G protein-coupled P2Y6 pyrimidoceptor protects colorectal cancerous epithelial cells from apoptosis: Is this receptor a novel target against colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4597.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".