Abstract B49: Using ionizing radiation and primary human esophageal adenocarcinoma xenograft models to interrogate tumor cell characteristics associated with tumor-initiating cells
Bibliographic record
Abstract
Abstract Radiotherapy is critical to the treatment of esophageal adenocarcinoma (EAC). However, with frequent recurrence and metastasis, five-year survival rates are only 13%. Clinical radioresistance is further evidenced by the fact that escalated doses increase toxicity without improving outcome. The cancer stem cell model may provide insight on the EAC cell of origin and thus, on clinically-observed radioresistance. Recent evidence has demonstrated a differential ability of EAC cells to seed tumors in mice, however a correlation between tumorigenicity and radioresistance in EAC has not been reported. Recently, sequencing and cross-checking of 14 commercially-available EAC cell lines revealed that these cell lines were in fact derived from other cancer types. These findings highlight the need for reliable models of EAC. We have developed mouse xenograft models of primary human EAC that recapitulated the original tumors in cellular differentiation and tumor architecture. Using these models, we compared the in vivo tumorigenicity of irradiated versus non-irradiated (control) tumors. We hypothesized that ionizing radiation would enrich the population of tumor-initiating cells (TIC) in xenograft tumors compared to non-irradiated tumors. Thus far, we are evaluating five primary xenograft models of human EAC that have been established in NODSCID mice. Treatment sensitivity testing has been performed on these five xenograft lines, and limiting dilution assays (LDA) have been performed on the first two. Initial experiments have revealed that xenograft Line 2 is significantly more radioresistant than the other four lines. LDA results on xenograft Line 1 revealed a TIC frequency of 1 in 20,089 in non-irradiated xenograft tumors and 1 in 40,620 in irradiated xenograft tumors. Line 2 revealed a TIC fraction of 1 in 434 non-irradiated tumors and 1 in 31,631 irradiated xenografts. These results suggest two Conclusions: (1) TIC frequency may be associated with relative radioresistance, since the radioresistant Line 2 appeared to be very tumorigenic; and (2) the comparison of TIC fractions in non-irradiated and irradiated xenograft tumors raises concerns that infiltrating mouse cells may dilute the TIC frequency through a radiation-induced inflammatory response. In subsequent LDAs, cells positive for the mouse-specific antigen H2k were depleted from the tumour cell suspension. Results from these LDAs are forthcoming, and will be presented at the meeting. In conclusion, preliminary LDA results have shown that the baseline TIC frequency in EAC xenografts is highly variable and might be related to radiosensitivity; our results suggest that this variability can be several orders of magnitude wider than previously reported. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B49.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".