Abstract 5152: The role of CCL21/CCR7 chemokine axis in breast cancer induced lymphangiogenesis
Bibliographic record
Abstract
Abstract Introduction: Cellular and molecular mechanisms in lymphatic metastasis, a common occurrence in mammary carcinoma, remain poorly defined. A bidirectional communication pathway between tumor cells and lymphatic endothelial cells at the tumor-vessel interface enables guidance of sprouting lymphatic vessels towards tumors and instructs tumor cells to migrate to remote sites. Based on recent findings indicating (1) high expression of the chemokine receptor CCR7 in tumors developing in lymphatic-rich areas, (2) involvement of CCR7 chemokine ligand, CCL21, in organ-selective breast cancer metastasis, and (3) high levels of production of the lymphangiogenic molecule vascular endothelial growth factor-C (VEGF-C) by COX-2 expressing breast cancer cell lines, we suggest that the aforementioned bidirectional communication is orchestrated at molecular level by the interplay between CCL21/CCR7 chemokine axis and VEGF-C. Methods and results: We used the highly metastastic, COX-2 expressing and VEGF-C producing human breast cancer cell line MDA-MB-231 and primary cultures of human dermal lymphatic microvascular endothelial cells (HMVEC-dLy) as our two cell models in vitro. The constitutive expression of CCR7 receptor in both cell lines was confirmed by real-time PCR at the mRNA level, and by Western Blot, immunostaining, and FACS analysis at the protein level. Also, CCL21 ligand was found to be expressed at protein and mRNA levels by both cell lines. The lymphangiogenic potential of the CCL21/CCR7 axis in vitro was demonstrated with HMVEC-dLy cells for a concentration dependent, exogenous ligand-induced (1) proliferation (BrdU colorimetric assay), (2) migration (Boyden chamber assay across 8 μm pores of microporous membranes), and (3) morphogenesis (tube formation assay on growth factor-reduced Matrigel). Both proliferation and migration increased 2-2.5 fold after stimulation with CCL21 ligand (200-350 ng/ml) and decreased 1.8-2 times under inhibitory conditions (10 μg/ml CCR7 antibody). Tubular network formation (quantified through imaging) by HMVEC-dLy at 8 hours incubation increased 1.6 times in the presence of CCL21 (300 ng/ml) compared to basal conditions. Tubular network formation was blocked after a prior treatment with CCR7 antibody (10 μg/ml). Further investigations are in progress to test that CCR7 positive tumor cells regulate VEGF-C activity, with an underlying assumption that VEGF-C expression is in fact stimulated by CCL21/CCR7 interaction. Conclusion: These results in our in vitro model reveal for the first time the promoting role of CCL21/CCR7 axis in breast cancer-associated lymphangiogenesis. (Supported by grants awarded by the Ontario Institute of Cancer Research and the Canadian Breast Cancer Foundation, Ontario Chapter, to PKL, and the Canadian Institutes of Health Research – Cancer Research and Technology Transfer scholarship to ETF). 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 5152. doi:10.1158/1538-7445.AM2011-5152
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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 | 0.001 |
| 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) | 0.003 | 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".