Characterization of hERG1 channel role in the regulation of the process of neo-angiogenesis: in vitro and in vivo studies.
Bibliographic record
Abstract
Sustained angiogenesis is a critical step in tumour progression; indeed the clinical success of angiogenesis inhibitors has confirmed this paradigm. However, the efficacy of anti-angiogenic therapy has been more challenging than expected, mainly due to intrinsic resistance to anti-angiogenic drugs. Hence the identification of novel mechanisms sustaining tumour angiogenesis, and the development of appropriate pharmacologic targeting of new angiogenesis-related molecules is a major challenge in cancer therapy.\nIn this thesis, we report a new mechanism that regulates angiogenesis in colorectal cancers (CRC). \nThe human ether-à-go-go related gene (hERG)1 K+ channel is up-regulated in human colorectal cancer cells and primary samples.\nBeyond its canonical role in excitability, hERG1 channel is emerging as a major regulator of intracellular signalling, in tumour cells. This role relies on its ability to assemble with partner proteins, and particularly adhesion receptors of the integrin family. In this thesis, we found that β1 integrin-mediated adhesion to the extracellular matrix (ECM) modulates secretion of vascular endothelial growth factor (VEGF)-A. This effect relies on an intermolecular cooperation between the β1 integrin, hERG1 channels and the p85 subunit of the phosphatidyl inositol-3-kinase (PI3K). Such cooperation is triggered by the ECM and leads to activation of Akt, which in turn increases the HIF-dependent VEGF-A transcription. The latter occurs through a mTOR- and FOXO- independent, NF-kB-activated regulation of HIF-1α and HIF-2α. \nMoreover, we examined the role of hERG1 in colorectal carcinogenesis in vivo, using two mouse models: Apcmin/+ and Azoxymethane-treated mice. \nColonic polyps of Apcmin/+ mice over-expressed m-ERG1 and their formation was reverted by the hERG1 blocker E4031. \nAzoxymethane was applied to either hERG1-transgenic mice, which over-express hERG1 in the mucosa of the large intestine, or wild type mice. A significant increase of both mucin-depleted foci and polyps in the colon of hERG1-transgenic mice was detected. \nBoth the intestine of transgenic mice and colonic polyps of Apcmin/+ showed an up-regulation of pAkt/VEGF-A and an increased angiogenesis, which were reverted by treatment with E4031, providing evidence that, also in vivo, the role of hERG1 in CRC carcinogenesis can be traced back to its role in the signalling pathways which regulate VEGF-A secretion and neo-angiogenesis.\nOn the whole, this study assigns a relevant role to hERG1 in the process of in vitro and in vivo colorectal carcinogenesis. hERG1 can be considered a “tumour progression” gene in vitro, since a complex comprising integrins and hERG1 channels strongly regulate angiogenesis and tumour progression in CRC cells model, as well as in vivo, since the channel strongly cooperates with genetic (loss of the tumour suppressor gene Apc) or environmental (chemical carcinogen) factors in triggering CRC progression in mouse CRC models.\nOur results indicate the use of hERG1 blocking drugs devoid of cardiac side effects as a novel anti-angiogenesis treatment of CRC, especially in those cases resistant to anti-VEGF-A drugs.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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".