Abstract
Recombinant granulocyte colony-stimulating factor (G-CSF) is used to accelerate recovery from chemotherapy-induced myelosuppression. G-CSF has been recently shown to stimulate angiogenesis mediated by several types of bone marrow-derived cell populations. To investigate whether G-CSF may alter tumor response to therapy, we studied Lewis lung and EMT/6 breast carcinomas in mice treated with paclitaxel (PTX) chemotherapy in combination with G-CSF. We compared the results obtained to mice treated with PTX and AMD3100, a small-molecule drug antagonist of CXCR4 which, like G-CSF, can be used to mobilize hematopoietic cells. We show that PTX combined with G-CSF treatment facilitates revascularization, leading to an improvement in blood perfusion in LLC tumors, and a decrease in hypoxia in EMT/6 tumors, thus enhancing tumor growth in comparison to PTX or PTX and AMD3100 therapies. We found that hemangiocytes but not Gr-1(+) CD11b(+) cells colonize EMT/6 tumors after treatment with PTX and G-CSF, but not PTX and AMD3100, and therefore may contribute to angiogenesis. However, increases in hemangiocyte colonization were not observed in LLC PTX and G-CSF-treated tumors, suggesting distinct mechanisms of tumor revascularization after G-CSF. Overall, our observations suggest that despite its known considerable clinical benefits, G-CSF might contribute to tumor revascularization by various mechanisms, and diminish the antitumor activity of chemotherapy, an effect that can be prevented by AMD3100.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / administration & dosage*
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Benzylamines
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Carcinoma, Lewis Lung / blood supply
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Carcinoma, Lewis Lung / drug therapy*
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Carcinoma, Lewis Lung / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Cyclams
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Drug Combinations
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Female
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Flow Cytometry
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Granulocyte Colony-Stimulating Factor / administration & dosage
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Granulocyte Colony-Stimulating Factor / adverse effects*
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Granulocyte Colony-Stimulating Factor / therapeutic use
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Heterocyclic Compounds* / administration & dosage
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Heterocyclic Compounds* / therapeutic use
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Humans
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Immunohistochemistry
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Inflammatory Breast Neoplasms / blood supply
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Inflammatory Breast Neoplasms / drug therapy*
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Inflammatory Breast Neoplasms / pathology
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Injections, Intraperitoneal
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Matrix Metalloproteinase 2 / analysis
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Matrix Metalloproteinase 2 / biosynthesis
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Mice
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Mice, Knockout
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Neovascularization, Pathologic* / drug therapy
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Neovascularization, Pathologic* / prevention & control
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Paclitaxel / administration & dosage*
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Receptors, CXCR4 / antagonists & inhibitors*
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Receptors, CXCR4 / metabolism
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Vascular Endothelial Growth Factor A / analysis
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Vascular Endothelial Growth Factor A / biosynthesis
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Benzylamines
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Cyclams
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Drug Combinations
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Heterocyclic Compounds
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Receptors, CXCR4
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Vascular Endothelial Growth Factor A
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Granulocyte Colony-Stimulating Factor
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Matrix Metalloproteinase 2
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Mmp2 protein, mouse
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Paclitaxel
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plerixafor