Abstract 636: Role of Prostaglandin E2 in breast-cancer associated lymphangiogenesis in an in vitro system
Bibliographic record
Abstract
Abstract Lymphatic metastasis is a common occurence in breast cancer. Molecular mechanisms in breast cancer-associated lymphangiogenesis and lymphatic metastasis are poorly defined. We had earlier shown that elevated cyclo-oxygenase (COX)-2 expression by human as well as murine breast cancer cells promotes tumor progression and metastasis by multiple mechanisms: inactivation of host anti-tumor immune cells, stimulation of tumor cell migration and tumor-associated angiogenesis. Furthermore, COX-2 was causally associated with increased VEGF-C expression/secretion in human and murine breast cancer cell lines, thus promoting tumor-associated lymphangiogenesis. VEGF-C production was partially dependent on endogenous PGE-2 mediated activation of EP4 receptors on breast cancer cells thus making EP4 a good therapeutic target. It was unclear whether tumor or host derived PGE-2 had any direct effect on lymphangiogenesis, and if so, whether EP4 receptors on lymphatic endothelial cells played any role. To address these questions, we devised an in vitro lymphangiogenesis assay using a LYVE-1 expressing rat mesenteric lymphatic endothelial cell line (RMLEC) plated on growth factor- reduced Matrigel. Endothelial tube formation by RMLEC was rapidly induced in 12-18 hours after plating on Matrigel even under serum-free conditions, whereas plating them on collagen gel even in the presence of serum did not induce any tube formation. This suggested the presence of some inducing factor(s) in the Matrigel, possibly also present in the ECM in vivo. Matrigel-induced tube formation was completely abrogated in the presence of COX 1/2 inhibitor indomethacin (10mM), COX-2 inhibitor NS-398 (15mM), and a selective EP4 antagonist CJ-042794 (2.5 mM). In each case, an additional presence of PGE2 (1 µM) or an EP4 agonist PGE-1 alcohol (1µM) completely restored the tube formation on matrigel. A similar restoration was also achieved in the presence of serum-free conditioned media (24 h culture) of a COX-2 expressing murine breast cancer cell line C3L5 that induces lymphangiogenesis in vivo. These results indicate the roles of tumor as well as host-derived PGE2 in inducing lymphangiogenesis possibly by activating COX-2/EP4 receptors on lymphatic endothelial cells. Further studies are in progress to identify the tube-inducing component(s) in the Matrigel and C3L5 cell conditioned medium. (Supported by grants from the Canadian Breast Cancer Foundation, Ontario chapter and the Ontario Institute of Cancer Research to PKL. The gift of the RMLEC from Dr Sophia Ran, Southern Illinois Univ School of Medicine is gratefully acknowledged). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 636.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| 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) | 0.002 | 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".