Activity of signaling pathways in hypoxic pancreatic and cervical tumor xenografts
Bibliographic record
Abstract
B193 Tumor hypoxia is widespread in different cancer types and has been associated with poor prognosis. Current monolayer cell culture models suggest that signaling pathways including Src, STAT3 and AKT influence the transcription activity of hypoxia inducible factor-1α (HIF-1α) which affects biological processes including tumor angiogenesis, metastasis and survival. We determined the activity of these signaling proteins in hypoxic tumor regions compared to non-hypoxic regions as well as global tumor response to continuous in vivo hypoxia. Tumor hypoxia was measured based on the histological distribution of the fluorescently labeled 2-nitroimidazole agent EF5 in four murine xenograft models. In air exposed mice, the percent of hypoxic EF5-stained tumor regions ranged from a mean of 14% (BxPC-3) to 48% (PANC-1) for subcutaneously grown pancreatic xenografts, and 20% (ME180) to 27% (SiHa) for orthotopically grown cervical xenografts. A doubling of EF5-stained regions was achieved in BxPC-3 tumors with continuous exposure of mice to 7% O 2 for 3 hours compared to air control. Individual EF5-stained serial tissue sections were co-labeled with single antibodies against signaling proteins. Immunofluorescence image analysis (labeled percent area x intensity) showed a significant increase in the level of total Src protein in EF5 tumor regions compared to non-EF5 regions in all four tumor models (p≤0.05, Wilcoxon test). Additionally, the levels of total and activated Src (Y419) doubled (p=0.03) in EF5 tumor regions compared to non-EF5 regions of mice exposed to low O 2 levels, suggesting that levels of Src protein and activity are hypoxia inducible. There was a strong co-localization of activated Src and focal adhesion kinase (Y861-FAK) in EF5-stained regions of BxPC-3 tumors (r=0.74, p=0.006) in mice exposed either to air or 7% O 2 . This suggests that the cellular adhesion substrate FAK is important in Src-mediated hypoxia signaling in vivo . In contrast, BxPC-3 tumor xenografts of mice exposed to 7% O 2 showed a decrease in levels of STAT3 (S727) activity (p=0.004, Mann-Whitney test) despite no changes in total STAT3 levels in the entire tumor area. The continuous exposure to 7% O 2 did not affect levels of AKT (S473) activity. These results suggest an important role of Src in hypoxia-responsive signaling in vivo . The increased expression and enhanced activity of Src family tyrosine kinases have been associated with carcinogenesis in different tumor types. Also, Src is a common substrate of oncogenic signaling downstream of several growth factor receptors including EGFR, PDGFR and Met, and impacts on tumor cell adhesion, migration and invasion. A therapeutic strategy involving the use of Src inhibitors might be successful at targeting tumor growth as well as hypoxia-induced processes which lead to increased tumor aggressiveness.
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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 | 0.000 | 0.000 |
| 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".