Examining the Effects of Endothelial BMPR2 Loss on Angiogenesis in Murine Metastatic Lung Tumours
Bibliographic record
Abstract
It is proposed that bone morphogenetic protein 9 (BMP9) may play a role in cancer development and tumour angiogenesis; however, its role has not been fully elucidated. Under normal conditions, BMP9 acts as a vascular quiescence factor (David et al., 2008); signalling through Type I and II receptors, including Bone Morphogenetic Protein Receptor II (BMPR-II) in the endothelium. However, these effects are highly context dependent. Previous reports examining the role of BMP9 in cancer have shown that BMP9 promotes tumour vascularization and can enhance the growth of ovarian tumours (Cunha et al. 2010, Herrera et al., 2009). The objective of this work is to determine if these contradictory effects are mediated by a loss of BMPR2 in the tumour vasculature endothelium. Adult C57/Bl6 mice, bearing a pulmonary endothelial-specific deletion of the gene encoding BMPR-II (Bmpr2EC-/-) and wildtype littermate controls (Bmpr2EC+/+), were administered syngeneic EO771 breast cancer cells into the mammary fat pad. These cells express red fluorescent protein (RFP) and were assayed for in vitro BMP9 responsiveness through qPCR, western blotting and proliferation assays. After four weeks, the primary tumour was resected to encourage lung metastasis. Four weeks after resection, study endpoint was reached, lungs were collected, and lung tumour burden was quantified as a measure of whole lung fluorescence. 2-photon confocal microscopy was used to quantify tumour burden and vascular network density in the explanted lungs. In vitro, stimulation of EO771 cells with BMP9 (10ng/mL) resulted in an increase in SMAD1/5/9 phosphorylation. However, this signalling response did not translate to a functional proliferative response to BMP9 treatment, relative to unstimulated controls. In vivo, no significant differences were observed in the growth of primary mammary tumours between Bmpr2EC+/+ and Bmpr2EC-/- mice (p=0.9). Lung metastasis burden was also not significantly different in mice lacking pulmonary endothelial ii Bmpr2, when compared to wildtype controls (p=0.2). Our findings suggest that pulmonary endothelial Bmpr2 loss enhances the growth of lung tumour metastases, and that growth is independent of any direct effects of BMP9 on EO771 proliferation. Ongoing studies are examining the effects of recombinant BMP9 administration on metastasis growth in this model, with and without endothelial Bmpr2 deletion.
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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 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".