Mesenchymal stem cell-derived interleukin-6 and vascular endothelial growth factor promote breast cancer cell migration.
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.
Cell Biology and Biotherapy Unit, INT-Fondazione Pascale, Naples, Italy.
Antonella
A
De Luca
Luana
L
Lamura
Marianna
M
Gallo
Veronica
V
Maffia
Nicola
N
Normanno
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D000068258:Bevacizumab; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002450:Cell Communication; D002465:Cell Movement / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D000068258:Bevacizumab; D017077:Culture Media, Conditioned; D015850:Interleukin-6; D020928:Mitogen-Activated Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D048051:p38 Mitogen-Activated Protein Kinases; D000093242:Interleukin-6 Inhibitors; C508600:IL6 protein, human; C467484:VEGFA protein, human