Abstract C235: Interleukin-6 secreted by cancer-associated fibroblasts mediates gemcitabine resistance in pancreatic cancer.
Bibliographic record
Abstract
Abstract Introduction: Pancreatic ductal adenocarcinoma is characterized by a dense stroma containing an abundance of cancer-associated fibroblasts (CAFs). It is also notably resistant to gemcitabine. We hypothesize that the large population of CAFs in pancreatic tumors secrete elevated levels of multiple soluble factors, which promote survival of pancreatic cancer cells and reduce their sensitivity to gemcitabine. Previously, we found that growth of MiaPaCa-2 and BxPC-3 tumors was suppressed with gemcitabine treatment, but that of tumors from MiaPaCa-2 and BxPC-3 co-injected with primary pancreatic CAFs was not. This suggests that the presence of CAFs causes pancreatic cancer cells to become more resistant to gemcitabine. Subsequent Affymetrix analyses showed that interleukin-6 (IL-6) is one of 382 genes that are differentially upregulated by >2-fold (P<0.05) in primary pancreatic CAFs as compared to normal fibroblasts. The objectives of the current study are to validate the expression/secretion of IL-6 as well as other components of the IL-6 signaling pathway, and to determine how IL-6 affects the sensitivity of pancreatic cancer cells to gemcitabine. Methods: Sixteen primary CAF lines were established in culture from resected pancreatic ductal adenocarcinoma tumor tissues. As well, eleven primary orthotopic tumor xenograft lines were established in SCID mice from the resected tissues. Subcutaneous tumors were also grown by injecting 5×106 MiaPaCa-2, BxPC-3, or Panc-1 pancreatic cancer cells into SCID mice. Using ELISA, the levels of IL-6, soluble IL-6 receptor (sIL-6R) and the soluble form of gp130 were evaluated in the primary CAFs and orthotopic tumor xenografts, as well as in several pancreatic cancer cell lines. Levels of mouse IL-6 in the serum of mice bearing orthotopic tumors and subcutaneous cell line xenografts were also assayed. Results: The levels of human IL-6 protein were 1.1- to 79-fold higher in the CAF lines than in normal human fibroblasts. However, human IL-6 protein was not detected in pancreatic cancer cell lines PK8, MiaPaCa-2, Panc-1, Capan-2, BxPC-3, or in normal human pancreatic ductal epithelial cells (HPDEs). The levels of mouse IL-6 protein were 1.2- to 94-fold higher in the serum of mice bearing orthotopic tumors as compared to the serum of normal healthy mice. Interestingly, no mouse IL-6 protein was detected in the serum of mice bearing subcutaneous cancer cell line tumors. Furthermore, high levels of mouse IL-6 (12–100 pg/mg) but not human IL-6 were evident in the lysates of the orthotopic tumors. Human sIL-6Rprotein levels were found to be high (24–65 pg/mg) in pancreatic cancer cell lines, but present only at low levels (∼12 pg/mg) in four of the sixteen CAF lines. It was also detected at 13–66 pg/mg in all of the orthotopic tumors. Soluble gp130 protein was observed at higher levels in the CAFs than in the pancreatic cancer cell lines. It was also detected in all of the orthotopic tumors. Conclusion: Our results demonstrate that CAFs are the major producers of IL-6 in pancreatic tumors. It is likely that IL-6 secreted by CAFs binds to IL-6 receptors on pancreatic cancer cells, resulting in the activation of downstream cell survival proteins. Co-culture experiments are underway to identify these proteins and to determine if inhibition of IL-6 signaling may increase the sensitivity of pancreatic cancer cells to gemcitabine. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C235.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".