Abstract
Several different cytokines and growth factors secreted by mesenchymal stem cells (MSCs) have been hypothesized to play a role in breast cancer progression. By using a small panel of breast cancer cell lines (MCF-7, T47D, and SK-Br-3 cells), we analyzed the role of interleukin-6 (IL-6) and vascular endothelial growth factor A (VEGF) in the cross-talk between MSCs and breast cancer cells. We performed migration assays in which breast cancer cells were allowed to migrate in response to conditioned medium from MSCs (MSCs-CM), in absence or in presence of the anti-VEGF antibody bevacizumab or an anti-IL-6 antibody, alone or in combination. We found that anti-VEGF and anti-IL-6 antibodies inhibited the migration of breast cancer cells and that the combination had an higher inhibitory effect. We next evaluated the effects of recombinant VEGF and IL-6 proteins on breast cancer cell growth and migration. IL-6 and VEGF had not significant effects on the proliferation of breast carcinoma cells. In contrast, both VEGF and IL-6 significantly increased the ability to migrate of MCF-7, T47D and SK-Br-3 cells, with the combination showing a greater effect as compared with treatment with a single protein. The combination of VEGF and IL-6 produced in breast cancer cells a more significant and more persistent activation of MAPK, AKT, and p38MAPK intracellular signaling pathways. These results suggest that MSC-secreted IL-6 and VEGF may act as paracrine factors to sustain breast cancer cell migration.
Copyright © 2012 Wiley Periodicals, Inc.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inhibitors / pharmacology
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Antibodies, Monoclonal, Humanized / pharmacology
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Antibodies, Neutralizing / pharmacology
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Bevacizumab
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Breast Neoplasms / genetics*
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Cell Communication
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Cell Movement / drug effects
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Culture Media, Conditioned / pharmacology
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Drug Synergism
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Interleukin-6 / antagonists & inhibitors
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Interleukin-6 / metabolism*
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Interleukin-6 / pharmacology
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Mesenchymal Stem Cells / metabolism*
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Mesenchymal Stem Cells / pathology
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / metabolism
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Recombinant Proteins / pharmacology
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Signal Transduction / drug effects
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Tumor Cells, Cultured
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Vascular Endothelial Growth Factor A / antagonists & inhibitors
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Vascular Endothelial Growth Factor A / metabolism*
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Vascular Endothelial Growth Factor A / pharmacology
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Angiogenesis Inhibitors
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Antibodies, Monoclonal, Humanized
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Antibodies, Neutralizing
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Culture Media, Conditioned
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IL6 protein, human
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Interleukin-6
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Recombinant Proteins
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VEGFA protein, human
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Vascular Endothelial Growth Factor A
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Bevacizumab
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases