Abstract
Colony-stimulating factor (CSF)-1 is the primary regulator of tissue macrophage production. CSF-1 expression is correlated with poor prognosis in breast cancer and is believed to enhance mammary tumor progression and metastasis through the recruitment and regulation of tumor-associated macrophages. Macrophages produce matrix metalloproteases (MMPs) and vascular endothelial growth factor, which are crucial for tumor invasion and angiogenesis. Given the important role of CSF-1, we hypothesized that blockade of CSF-1 or the CSF-1 receptor (the product of the c-fms proto-oncogene) would suppress macrophage infiltration and mammary tumor growth. Human MCF-7 mammary carcinoma cell xenografts in mice were treated with either mouse CSF-1 antisense oligonucleotide for 2 weeks or five intratumoral injections of either CSF-1 small interfering RNAs or c-fms small interfering RNAs. These treatments suppressed mammary tumor growth by 50%, 45%, and 40%, respectively, and selectively down-regulated target protein expression in tumor lysates. Host macrophage infiltration; host MMP-12, MMP-2, and vascular endothelial growth factor A expression; and endothelial cell proliferation within tumors of treated mice were decreased compared with tumors in control mice. In addition, mouse survival significantly increased after CSF-1 blockade. These studies demonstrate that CSF-1 and CSF-1 receptor are potential therapeutic targets for the treatment of mammary cancer.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Division
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Down-Regulation
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Endothelial Cells / metabolism
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Endothelial Cells / pathology
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Female
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Humans
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Macrophage Colony-Stimulating Factor / antagonists & inhibitors*
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Macrophage Colony-Stimulating Factor / genetics
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Macrophage Colony-Stimulating Factor / metabolism
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Macrophages / metabolism
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Macrophages / pathology
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Mammary Neoplasms, Animal / genetics
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Mammary Neoplasms, Animal / pathology
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Mammary Neoplasms, Animal / prevention & control*
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Matrix Metalloproteinase 12
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Matrix Metalloproteinase 2 / metabolism
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Metalloendopeptidases / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Oligonucleotides, Antisense / therapeutic use*
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Proto-Oncogene Mas
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RNA, Small Interfering / therapeutic use*
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Receptor, Macrophage Colony-Stimulating Factor / antagonists & inhibitors*
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Receptor, Macrophage Colony-Stimulating Factor / genetics
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Receptor, Macrophage Colony-Stimulating Factor / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Survival Rate
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Tumor Cells, Cultured
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Vascular Endothelial Growth Factor A / metabolism
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Xenograft Model Antitumor Assays
Substances
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MAS1 protein, human
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Oligonucleotides, Antisense
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Proto-Oncogene Mas
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RNA, Small Interfering
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Vascular Endothelial Growth Factor A
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Macrophage Colony-Stimulating Factor
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Receptor, Macrophage Colony-Stimulating Factor
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Metalloendopeptidases
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Matrix Metalloproteinase 2
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MMP12 protein, human
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Matrix Metalloproteinase 12