Thrombospondin-1 receptor mediates autophagy of RAS-expressing cancer cells and triggers tumour growth inhibition.
Bibliographic record
Abstract
BACKGROUND: The anti-angiogenic activity of thrombospondin-1 (TSP-1) is suppressed in cancer cells, fact which has generated considerable interest in generating the respective therapeutic mimetics. These efforts were almost exclusively centered on peptides targeting CD36, the known TSP-1 receptor. Since the effects of these agents were less dramatic than those of full-length. TSP-1 questions could be raised about the cancer-related roles of additional TSP-1 domains and receptors, such as CD47, which bind the C-terminal sequences of this protein. MATERIALS AND METHODS: The MDFB6 and B6ras cell lines were treated with the anti-CD47 antibody or C-terminal TSP-1 peptide 4N1K and cell viability was monitored using Aqueous Non-Radioactive Cell Proliferation Assay, DNA fragmentation, caspase-3 activation, and cell membrane depolarization assays. The cells were also stained with acridine orange and the anti-LC3 antibody to detect autophagy. B6ras tumours were generated in SCID-NOD mice and tumour responses to injections of the 4N1K peptide were recorded over time. RESULTS: We demonstrated a selective loss of viability of RAS-transformed cells upon ligation of the CD47 receptor. Affected cells did not exhibit hallmarks of apoptosis, but instead were stained with acridine orange and exhibited a punctuate pattern of immunoreactivity for LC3, both features of autophagy. The 4N1K peptide administration also caused a modest but specific and significant tumour growth inhibition in vivo. CONCLUSION: Our study offers an additional mechanism whereby TSP-1 affects tumour cells directly, in an angiogenesis-independent and CD47-mediated manner. This is consistent with near complete loss of TSP-1 expression in RAS-transformed cells and may open new avenues for therapies involving TSP-1 peptides, in a subset of tumours.
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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".