MMP-14 Mediates Migration of Acute Myelogenous Leukemia Cells
Bibliographic record
Abstract
Abstract Matrix metalloproteinase (MMP)-14 expression correlates with progression and metastasis of multiple tumor cell types and is a major mediator of cell migration and invasion. MMP-14 possesses a trans-membrane domain that tethers the enzyme to the plasma membrane and not only activates proMMP-2 but also degrades extracellular matrix (ECM) by pericellular proteolysis and cleaves several non-ECM molecules, including adhesion molecules and chemokines. To assess the role of MMP-14 in leukemic dissemination we evaluated its expression in myeloid cell lines and primary acute myelogenous leukemic (AML) samples. Using RT-PCR, flow cytometry and Western blotting we found that MMP-14 is highly expressed in leukemic myeloid cell lines THP-1, U937, HEL and K562; and primary samples from 37 out of 40 patients (pts) diagnosed with AML (WHO classification, AML with recurrent cytogenetic translocations: 9 pts; AML with multilineage dysplasia: 4 pts; AML not otherwise categorized: 27 pts). Moreover, primary AML blasts secreted the 72 kDa proenzyme form of MMP-2 into media (zymography) which became activated after co-culture of AML blasts with bone marrow (BM) stromal cells. This activation was inhibited by the potent MMP-14 inhibitor epigallocatechin-3-gallate (EGCG). We also found that migration of primary AML cells (trans-Matrigel invasion assay) was inhibited by EGCG; and silencing of MMP-14 by transfecting THP-1 cells and AML blasts with MMP-14 siRNA oligonucleotides resulted in reduced trans-Matrigel migration of these cells. Given that AML blasts constitutively secrete TNF-α, we confirmed that AML blasts express mRNA for TNF-α as well as its receptors TNFR1 and TNFR2; and TNF-α levels are elevated in the plasma of AML patients. However, we demonstrated that recombinant human (rh) TNF-α further upregulated MMP-14 expression in AML blasts (RT-PCR, Western blot) and increased its incorporation into membrane lipid rafts (confocal microscopy). Moreover, rh TNF-α- stimulated AML blasts were found to be more potent activators of pro-MMP-2 than unstimulated cells (zymography), indicating that activation may occur via upregulation of MMP-14; had significantly higher migration which was inhibited by EGCG and also by the TNF-α receptor inhibitor Enbrel; and rh TNF-α had no effect on the migration of MMP-14 siRNA-silenced AML cells. Other factors tested, for example, SDF-1, IL-1 and TGF-β, had no effect on MMP-14 expression in AML cells (flow cytometry). In conclusion, we report here for the first time that MMP-14 is expressed in AML blasts and is modulated by TNF-α. We suggest that, by pericellular degradation of ECM and activation of latent MMP-2 secreted by AML blasts, MMP-14 may contribute to the highly proteolytic BM microenvironment in AML and the invasive phenotype of this malignancy.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.003 | 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".