Abstract 3434: Lipopoylsaccharide promotes human esophageal cancer cell metastatic potential via the selectin/sialyl Lewis X axis
Bibliographic record
Abstract
Abstract Background: Emerging data suggest that post-operative infections may increase esophageal cancer recurrence, possibly accounting for the poor prognosis associated with this malignancy. We have previously shown that lipopolysaccharide (LPS), a gram-negative bacterial antigen, injected into mice increases in vivo cancer cell adhesion to the hepatic sinusoids. However, the influence of LPS directly on the cancer cell is unknown. We thus sought to elucidate the direct impact of LPS and its sole trans-membrane receptor, Toll-Like Receptor 4 (TLR4) on human esophageal cancer cell metastatic potential. Methods: C57BL/6 mice were prepared for hepatic intravital microscopy and received intra-arterial inoculations with highly metastatic human esophageal squamous cells (HKESC-2; 1.5×106 cells/100μl) pre-incubated in LPS (0.1 μg/ml x 48hrs) or control media. HKESC-2-sinusoidal endothelial cell interactions were quantified with direct in vivo visualization of the hepatic sinusoids. In vitro static adhesion assay was use to measure cancer cell adhesion to fibronectin, collagen I and IV. SB203580, a p38 antagonist, was use to block LPS signaling. Two important adhesion molecules we have previously shown to be involved in the adhesion of these cancer cells to hepatic sinusoids, selectins and sialyl Lewis X (sLeX), were blocked using murine i.v. injection of fucoidin and incubation of cancer cells with blocking antibodies respectively. Results are presented as mean +/− SEM and MWU-test determined significance (* p<0.05). Results: HKESC-2 cells express TLR4 by flow cytometry and RT-PCR respectively. Immunoblots of LPS incubated HKESC-2 cells revealed increased phosphorylation of p38 MAP Kinase, an intracellular TLR4 downstream signaling molecule. Thus treated cells had a 2-fold increase in vitro adhesion to fibronectin but not to Collagen 1 or 4, an effect that was reversed by inhibition of p38 phosphorylation. Murine hepatic intravital microscopy demonstrated that LPS treated esophageal cancer cells had a 2.3 fold increase in adhesion to sinusoidal endothelium as compared to control (cells/field of view: 33.2+/−3.6 vs. 14.2 +/−0.5)*. This LPS-facilitated in vivo adhesion was attenuated by blockade of selectins and sLeX (7.7 +/− 0.4*; 14.37 +/− 0.8*). Conclusion: Using a physiologically relevant in vivo model of the early steps of cancer metastasis we have demonstrated that LPS-TLR4 mediated inflammation increased the metastatic potential of human esophageal cancer cells, at least partially through increased selectin-sialyl Lewis X binding. These findings identify LPS-TLR4 binding as a potential therapeutic target for the treatment and prevention of metastasis. 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 3434.
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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) | 0.005 | 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".