Malignant hematopoietic cells induce an increased expression of VEGFR-1 and VEGFR-3 on bone marrow endothelial cells via AKT and mTOR signalling pathways
Copyright policy )Malignant hematopoietic cells induce an increased expression of VEGFR-1 and VEGFR-3 on bone marrow endothelial cells via AKT and mTOR signalling pathways
Angiogenesis plays a significant role in a variety of malignant hematologic diseases, and it is recognized that it has prognostic value. However, the cellular mechanisms by which malignant hematologic cells induce angiogenesis are not well understood. In order to investigate the role of cells from B-cell chronic lymphocytic leukemia (B-CLL) and multiple myeloma (MM) in angiogenesis on human bone marrow endothelial cells (HBMEC), we analyzed the impact of factors secreted by B-CLL cells and by MM cells on HBMEC capillary tube formation on matrigel. It was found that, in addition to the secretion of angiogenic factors VEGF and b-FGF by B-CLL and MM cells, MM cells (but not B-CLL cells) induced a dramatic increase in expression of VEGFR-1 and VEGFR-3 on human bone marrow endothelial cells (HBMEC). It would seem that this increase in VEGFR-3 occurred via the ERK and mTOR pathways, since their respective inhibitors U0126, LY294002 or rapamycin were responsible for a decrease of VEGFR-3. In response to MM cells-increased VEGF receptors on HBMEC, endothelial cell migration was enhanced in a wound artificially produced in a semi-confluent HBMEC culture, a phenomenon which was also down-regulated by the same inhibitors that reversed the increase in VEGF receptors. The present study suggests that, in addition to the classic angiogenic pathway, another mechanism related to an increased expression of VEGFRs on HBMEC might exist in malignant hematopoietic angiogenesis.
- Sorbonne Paris Cité France
- Sorbonne University France
Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-1, TOR Serine-Threonine Kinases, Endothelial Cells, Bone Marrow Cells, Vascular Endothelial Growth Factor Receptor-3, Leukemia, Lymphocytic, Chronic, B-Cell, Culture Media, Tumor Cells, Cultured, Humans, Fibroblast Growth Factor 2, Multiple Myeloma, Protein Kinase Inhibitors, Protein Kinases, Proto-Oncogene Proteins c-akt, Signal Transduction
Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-1, TOR Serine-Threonine Kinases, Endothelial Cells, Bone Marrow Cells, Vascular Endothelial Growth Factor Receptor-3, Leukemia, Lymphocytic, Chronic, B-Cell, Culture Media, Tumor Cells, Cultured, Humans, Fibroblast Growth Factor 2, Multiple Myeloma, Protein Kinase Inhibitors, Protein Kinases, Proto-Oncogene Proteins c-akt, Signal Transduction
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