Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony-stimulating factor-1 receptor.
Invasion of human breast cancer cells in vivo requires both paracrine and autocrine loops involving the colony-stimulating factor-1 receptor.
复制标题
DOI：
10.1158/0008-5472.can-09-1868
复制
发表时间：
2009-12-15
期刊：
影响因子：
11.2
通讯作者：
Condeelis JS
中科院分区：
文献类型：
--
作者：
Patsialou A;Wyckoff J;Wang Y;Goswami S;Stanley ER;Condeelis JS
集落刺激因子-1（CSF-1）及其受体（CSF-1 R）与包括乳腺癌在内的多种癌症的发病机制和进展有关。这是基于侵袭性疾病患者血清中高水平的循环CSF-1和肿瘤组织中增加的CSF-1 R染色。然而，还没有直接的体内研究来确定CSF-1自分泌信号环是否在体内人乳腺癌细胞中起作用以及它是否有助于侵袭。最近，在小鼠和大鼠模型中，已经表明侵袭和转移是由肿瘤细胞和宿主巨噬细胞之间的EGF/CSF-1旁分泌环驱动的。在这种巨噬细胞依赖性侵袭中，肿瘤细胞分泌CSF-1和正义EGF，而巨噬细胞分泌EGF和正义CSF-1。在这里，我们测试的假设，在人类乳腺肿瘤的表达的CSF-1配体和其受体在肿瘤细胞导致CSF-1/CSF-1 R自分泌环，这有助于人类乳腺肿瘤的侵袭性表型。在SCID小鼠中使用MDA-MB-231细胞衍生的乳腺肿瘤，我们在此首次在体内显示，人乳腺肿瘤模型中的侵袭依赖于宿主巨噬细胞的旁分泌信号传导以及涉及肿瘤细胞本身的自分泌信号传导。特别地，我们表明，自分泌对侵袭的贡献通过肿瘤微环境诱导的CSF-1 R表达的上调（经由转化生长因子-β1）在体内特异性放大。
Colony stimulating factor-1 (CSF-1) and its receptor (CSF-1R) have been implicated in the pathogenesis and progression of various types of cancer, including breast cancer. This is based on high levels of circulating CSF-1 in patient sera with aggressive disease and increased CSF-1R staining in the tumor tissues. However, there have been no direct in vivo studies to determine whether a CSF-1 autocrine signaling loop functions in human breast cancer cells in vivo and whether it contributes to invasion. Recently, in mouse and rat models, it has been shown that invasion and metastasis are driven by an EGF/CSF-1 paracrine loop between tumor cells and host macrophages. In this macrophage-dependent invasion, tumor cells secrete CSF-1 and sense EGF, while the macrophages secrete EGF and sense CSF-1. Here we test the hypothesis that, in human breast tumors the expression of both the CSF-1 ligand and its receptor in tumor cells leads to a CSF-1/CSF-1R autocrine loop which contributes to the aggressive phenotype of human breast tumors. Using MDA-MB-231 cell derived mammary tumors in SCID mice we show here for the first time in vivo that invasion in a human mammary tumor model is dependent on both paracrine signaling with host macrophages as well as autocrine signaling involving the tumor cells themselves. In particular we show that, the autocrine contribution to invasion is specifically amplified in vivo through a tumor microenvironment induced upregulation of CSF-1R expression via the transforming growth factor-β1.