Colony-stimulating factor-1 blockade by antisense oligonucleotides and small interfering RNAs suppresses growth of human mammary tumor xenografts in mice
Colony-stimulating factor-1 blockade by antisense oligonucleotides and small interfering RNAs suppresses growth of human mammary tumor xenografts in mice
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DOI：
10.1158/0008-5472.can-04-0961
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发表时间：
2004-08-01
期刊：
影响因子：
11.2
通讯作者：
Abraham, D
中科院分区：
文献类型：
--
作者：
Aharinejad, S;Paulus, P;Abraham, D
集落刺激因子（CSF）-1是组织巨噬细胞产生的主要调节因子。CSF-I表达与乳腺癌的不良预后相关，并且被认为通过募集和调节肿瘤相关巨噬细胞来促进乳腺肿瘤进展和转移。巨噬细胞产生基质金属蛋白酶（MMP）和血管内皮生长因子，这是至关重要的肿瘤侵袭和血管生成。鉴于CSF-1的重要作用，我们假设CSF-1或CSF-1受体（c-fms原癌基因的产物）的阻断将抑制巨噬细胞浸润和乳腺肿瘤生长。小鼠中的人MCF-7乳腺癌细胞异种移植物用小鼠CSF-1反义寡核苷酸处理2周或5次瘤内注射CSF-1小干扰RNA或c-fms小干扰RNA。这些治疗分别抑制乳腺肿瘤生长50%、45%和40%，并选择性下调肿瘤裂解物中的靶蛋白表达。宿主巨噬细胞浸润;宿主MMP-12、MMP-2和血管内皮生长因子A的表达;以及治疗小鼠肿瘤内的内皮细胞增殖与对照小鼠肿瘤相比降低。此外，CSF-1阻断后小鼠存活率显著增加。这些研究表明，CSF-1和CSF-1受体是治疗乳腺癌的潜在治疗靶点。
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.