SC-36 * RECIPROCAL INTERACTION OF PGE2 AND WNT SIGNALING REGULATES CANCER STEM CELLS IN GLIOBLASTOMA
Bibliographic record
Abstract
The concept of oncogene addiction presupposes that cancer cells require certain dominant oncogenic signals for growth and survival. A profound implication of this hypothesis is that antagonizing this crucial pathway should have significant effects on cancer cells, while sparing normal cells that are not similarly addicted. Clinically, the recognition of oncogenes to which a cancer is addicted could have profound resonance for targeted cancer therapy. The Wnt signaling pathway has recently been described to be constitutively activated in a subgroup of glioblastomas. Here, we performed a systematic review of high-throughput screens of CSC and physiologic stem cell systems to identify possible mediators of the stem cell phenotype in glioblastoma. Of the agents identified in multiple screens, we chose to study indomethacin, a chemical inhibitor of cyclooxygenase-2, because of the well described role of COX-2 in stem cell maintenance and of prostaglandin E2 (PGE2) in glioma biology. We then found COX-2 to be expressed in glioma stem cells (GSCs), but not in normal adult neural stem cells. Activation of COX-2 signaling in vitro resulted in increased GSC proliferation, while antagonism of COX-2 using indomethacin or siRNA inhibits GSC proliferation and self-renewal. PGE2 further directs GSCs activation through its aberrant activation of the Wnt/β-catenin pathway, which then induces COX-2 expression. Blockade of the reciprocal PGE2/β-catenin signaling cycle results in inhibition of GSC proliferation, and loss of markers of stem-ness. In vivo, concurrent administration of the COX-2 antagonist, celecoxib, and the Wnt inhibitor, LGK974, enhanced the activity of temozolomide in a mouse glioblastoma xenograft model, through its antagonism of CSCs. Our findings demonstrate a central role for COX-2 and Wnt signaling in maintenance of the CSC phenotype in glioblastoma, and suggest that disruption of their reciprocal interaction has therapeutic potential in glioblastoma.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".