Pigment Epithelium-Derived Factor Stimulates Tumor Macrophage Recruitment and Is Downregulated by the Prostate Tumor Microenvironment
Pigment Epithelium-Derived Factor Stimulates Tumor Macrophage Recruitment and Is Downregulated by the Prostate Tumor Microenvironment
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DOI：
10.1593/neo.92046
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发表时间：
2010-04-01
期刊：
影响因子：
4.8
通讯作者：
Bergh, Anders
中科院分区：
文献类型：
--
作者：
Halin, Sofia;Rudolfsson, Stina Haggstrom;Bergh, Anders
色素上皮衍生因子（PEDF）是一种有效的血管生成抑制剂，但它是否对肿瘤微环境有额外的影响在很大程度上是未知的。我们发现原位MatLyLu大鼠前列腺肿瘤中PEDF的过度表达增加了肿瘤巨噬细胞的募集。表达诱导型一氧化氮合酶（细胞毒性M1巨噬细胞的标志物）的巨噬细胞的分数增加，表明PEDF可增强抗肿瘤免疫。此外，PEDF过表达减少了肿瘤和周围正常组织中的血管生长，减缓了肿瘤生长，并减少了淋巴结转移。相反，肿瘤外淋巴管生成增加。PEDF的表达，由于未知的原因，往往减少或丢失在前列腺肿瘤的进展。当AT-1大鼠前列腺肿瘤细胞，表达高水平的PEDF信使RNA（mRNA）和蛋白质，被注射到前列腺，PEDF是显着下调，表明在微环境中的因素抑制其表达。一种这样的因子可以是巨噬细胞衍生的肿瘤坏死因子α（TNF α）。一部分积聚的巨噬细胞表达TNF α，TNF α治疗下调体外前列腺AT-1肿瘤细胞和体内大鼠腹侧前列腺中PEDF蛋白和mRNA的表达。PEDF在前列腺肿瘤中显然具有多种作用：它抑制血管生成和转移，但也引起巨噬细胞积聚。积聚的巨噬细胞可以抑制肿瘤生长，但它们也可以抑制PEDF并增强淋巴血管生成，并以这种方式最终增强肿瘤生长。
Pigment epithelium-derived factor (PEDF) is a potent inhibitor of angiogenesis but whether it has additional effects on the tumor microenvironment is largely unexplored. We show that overexpression of PEDF in orthotopic MatLyLu rat prostate tumors increased tumor macrophage recruitment. The fraction of macrophages expressing inducible nitric oxide synthase, a marker of cytotoxic M1 macrophages, was increased, suggesting that PEDF could enhance antitumor immunity. In addition, PEDF overexpression reduced vascular growth both in the tumor and in the surrounding normal tissue, slowed tumor growth, and decreased lymph node metastasis. Contrary, extratumoral lymphangiogenesis was increased. PEDF expression is, for reasons unknown, often decreased or lost during prostate tumor progression. When AT-1 rat prostate tumor cells, expressing high levels of PEDF messenger RNA (mRNA) and protein, were injected into the prostate, PEDF is markedly downregulated, suggesting that factors in the microenvironment suppressed its expression. One such factor could be macrophage-derived tumor necrosis factor alpha (TNF alpha). A fraction of the accumulating macrophages expressed TNF alpha, and TNF alpha treatment downregulated the expression of PEDF protein and mRNA in prostate AT-1 tumor cells in vitro and in the rat ventral prostate in vivo. PEDF apparently has multiple effects in prostate tumors: it suppresses angiogenesis and metastasis, but it also causes macrophage accumulation. Accumulating macrophages may inhibit tumor growth, but they may also suppress PEDF and enhance lymph angiogenesis and, in this way, eventually enhance tumor growth.