Abstract 4409: Assessment of sonic hedgehog pathway inhibition in a novel orthotopic xenograft bladder cancer murine model
Bibliographic record
Abstract
Abstract Purpose of the study: To develop a reliable and reproducible bladder cancer murine model for the evaluation of the SHH pathway. Introduction: The sonic hedgehog (SHH) signaling pathway has been shown to play an integral role in the maintenance and progression of bladder cancer. Smoothened inhibitors are currently used in the clinic for treatment of some skin cancers, however they have failed to be effective in bladder cancers in vitro. Blocking alternative downstream molecules of the SHH pathway may be an efficacious strategy for bladder cancer treatment. In vitro assays possess a number of limitations such as environmental differences, loss of heterogenicity and vascularization and artificial levels of growth factors and cytokines within the cell culture media. To overcome this animal models are needed to facilitate the study of carcinogenesis mechanisms. A new bladder cancer model is now required to evaluate experimental therapeutics as previous animal models have utilized the mistakenly identified cervical cancer cell line KU7. Methods: A novel orthotopic murine bladder cancer model was developed to assess the role of the SHH signalling pathway in tumor growth and disease progression. The model comprises the instillation of luciferase-expressing UM-UC3 human transitional cell carcinoma cells into the bladder of athymic nude mice following a poly-L-lysine irrigation of the bladder. Tumors are measured by bioluminescent imaging after intra-peritoneal injection of luciferin. Antisense oligonucleotides (ASO) targeted to the SHH pathway transcription factors, Gli family zinc fingers 1 and 2 (Gli1, Gli2), were assessed in this model. Immunohistochemistry (IHC) of proteins in the SHH pathway were evaluated and compared to our in-house tissue microarray (TMA) of clinical bladder cancer samples. Results: Tumors in this model grew in an average period of time of 40 days with high rates of engraftment and reproducibility. In vitro analysis of SHH pathway inhibition showed a decrease in bladder cancer cell viability and increase in apoptosis following Gli ASO treatment. This effect bypasses smoothened protein regulation which was found to be ineffective in some cell lines. Gli ASO treatment reduced tumor size, and prevented further growth, of UM-UC3 bladder cancers in this mouse model. IHC confirmed Gli2 knock-down and showed increased apoptosis and decreased proliferation in the in vivo tumors. Comparison of modelled tumors to clinical samples showed an increased and diffused Gli2 staining throughout the tissue in both cases. Conclusions: A murine intravesical model consisting of human tumors provides a robust and effective in vivo system for the assessment of cancer inhibiting treatments. Gli2 ASO proved to be a promising treatment for bladder cancer by inhibiting tumor growth and disease progression. Citation Format: Peter A. Raven, Sebastian Frees, Betty Zhou, Claudia Chavez-Munoz, Michael Cox, Alan So. Assessment of sonic hedgehog pathway inhibition in a novel orthotopic xenograft bladder cancer murine model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4409.
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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 | 0.000 |
| 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".