Abstract 1092: Insulin-like growth factors modulate chemosensitivity to cisplatin and 5-fluorouracil in human esophageal cell lines
Bibliographic record
Abstract
Abstract Resistance to chemotherapy remains a major obstacle to survival of patients with esophageal adenocarcinoma (EADC). The aim of this study was to evaluate whether insulin-like growth factors (IGFs), recently implicated in the molecular pathogenesis of EADC, modulate chemosensitivity to Cisplatin (CDDP) and 5-Fluoruracil (5-Fu), two agents widely used in current clinical practice. Expression of IGF1, its receptor (IGF1R), and IGF2 (mRNA and protein) were studied using quantitative (real-time) PCR and Western blot in human esophageal cell lines: Het1A (derived from immortalized normal esophageal epithelium), OE33 and JHEsoAd1 (each derived from a primary EADC). For each cell line, the effect of various concentrations of IGFs, CDDP and 5-Fu, alone and in combination, on cell proliferation and clonogenicity were evaluated by standard MTT and colony formation assays, respectively. Changes in expression of 84 critical genes downstream from IGF1R were studied by PCR-array. Relative to Het1A, IGF1 and IGF2 mRNA were significantly (P<0.05) underexpressed by OE33; by contrast, JHEsoAd1 underexpressed IGF1 but overexpressed IGF2. Administration of either IGF1 (250ng/ml) or IGF2 (500ng/ml) to cell cultures resulted in increased cellular proliferation of JHEsoAD1 cells (after IGF1: 1.24+/-0.05 vs. 1.00+/-0.00 untreated, P<0.01; after IGF2: 1.15+/-0.06 vs. 1.00+/-0.06 untreated, P<0.05). As expected, cell proliferation and clonogenicity of all cell lines were inhibited by CDDP and/or 5-FU (at all dosages ranging from 1-4ug/ml). However, these cytotoxic effects were overcome by the administration of either IGF1 or IGF2 with the exception of: 1) JHEsoAd1 cells treated with CDDP, where IGF2 administration further reduced cellular proliferation (0.35+/-0.06 vs. 0.53+/-0.03 for cells treated with CDDP alone; P<0.05), and 2) JHEsoAd1 cells treated with 5-Fu, where IGF1 administration significantly reduced clonogenicity (0.07+/-0.07 vs. 0.49+/-0.06 for cells treated with 5-Fu alone; P<0.05). PCR-array analysis revealed up-regulation (Het1A and JHEsoAd1) and down-regulation (OE33 and JHEsoAd1) of selected PI3K/AKT pathway genes following IGF1 and IGF2 therapy. These pre-clinical studies confirm a central role for the IGF axis in esophageal tumor biology, with potential for IGFs to enhance the cytotoxic efficacy of standard chemotherapeutic agents in esophageal cell lines. The identification of novel molecular regulatory pathways downstream from IGF1R modulated by IGF therapy may well inform future cytotoxic and targeting strategies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1092. doi:10.1158/1538-7445.AM2011-1092
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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 | 0.001 |
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".