MFG-E8/lactadherin promotes tumor growth in an angiogenesis-dependent transgenic mouse model of multistage carcinogenesis
MFG-E8/lactadherin promotes tumor growth in an angiogenesis-dependent transgenic mouse model of multistage carcinogenesis
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DOI：
10.1158/0008-5472.can-07-0165
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发表时间：
2007-07-15
期刊：
影响因子：
11.2
通讯作者：
Udey, Mark C.
中科院分区：
文献类型：
--
作者：
Neutzner, Melanie;Lopez, Theresa;Udey, Mark C.
血管生成在肿瘤生物学中的相关性以及作为治疗靶点的相关性已经得到充分确立。MFG-E8（也称为乳粘附素）和发育内皮基因座1（Del 1）构成了一个调节血管生成的α（v）β（3）/β（5）配体的双基因家族。在鼠肿瘤细胞系中检测到MFG-E8 mWNA后，我们试图确定MFG-ES是否影响Rip 1-Tag 2转基因小鼠的肿瘤发生，Rip 1-Tag 2转基因小鼠是一种血管生成至关重要的癌症模型。与正常胰腺相比，MFG-E8 mRNA和蛋白在Rip 1-Tag 2小鼠的血管生成胰岛和肿瘤中增加。与对照Rip 1-Tag 2小鼠相比，MFGE 8缺陷型Rip 1-Tag 2小鼠血管生成胰岛和肿瘤负荷的频率降低。侵袭性癌在MFG-E8缺陷型小鼠中的代表性较低，但这两种品系的肿瘤频率和存活率相当。MFG-E8的缺乏也导致肿瘤血管通透性的降低，而血管形态没有明显变化。在血管生成的胰岛中观察到增殖减少，在胰岛和肿瘤中检测到凋亡细胞增加。在MFG-E8缺陷小鼠中也检测到编码促血管生成蛋白（包括血管生成胰岛中的FGF 2和血管生成胰岛和肿瘤中的Dell）的mmRNA的补偿增加。MFG-ES及其同源物Dell可能代表肿瘤和其他血管生成突出的疾病中的相关靶标。
The relevance of angiogenesis in tumor biology and as a therapeutic target is well established. MFG-E8 (also termed lactadherin) and developmental endothelial locus 1 (Del1) constitute a two-gene family of alpha(v)beta(3)/beta(5) ligands that regulate angiogenesis. After detecting MFG-E8 mWNA in murine tumor cell lines, we sought to determine if MFG-ES influenced tumorigenesis in Rip1-Tag2 transgenic mice, a cancer model in which angiogenesis is critical. MFG-E8 mRNA and protein were increased in angiogenic islets and tumors in Rip1-Tag2 mice compared with normal pancreas. Frequencies of angiogenic islets and tumor burdens were decreased in MFGE8-deficient Rip1-Tag2 mice compared with those in control Rip1-Tag2 mice. Invasive carcinomas were modestly under-represented in MFG-E8-deficient mice, but tumor frequencies and survivals were comparable in these two strains. Absence of MFG-E8 also led to decreases in tumor vascular permeability without obvious changes in vascular morphology. Decreased proliferation was noted in angiogenic islets and increases in apoptotic cells were detected in islets and tumors. Compensaton increases in mmRNA encoding proangiogenic proteins, including FGF2, in angiogenic islets, and Dell, in angiogenic islets and tumors, were also detected in MFG-E8-deficient mice. MFG-ES and its homologue Dell may represent relevant targets in cancer and other diseases in which angiogenesis is prominent.