Expression of HIF‐1α by human macrophages: implications for the use of macrophages in hypoxia‐regulated cancer gene therapy
Expression of HIF‐1α by human macrophages: implications for the use of macrophages in hypoxia‐regulated cancer gene therapy
复制标题
人类巨噬细胞表达 HIF-1α：对使用巨噬细胞进行缺氧调节癌症基因治疗的影响
作者：
B. Burke;N. Tang;K. Corke;D. Tazzyman;K. Ameri;M. Wells;C. Lewis
大量的单核细胞从血液中渗出到人类肿瘤中，在那里它们分化成巨噬细胞。在乳腺癌和前列腺癌中，这些细胞聚集在低氧张力（缺氧）区域，在那里它们通过上调一种或多种缺氧诱导因子（HIF）对缺氧作出反应。然后这些物质在细胞核中积累，并与称为缺氧反应元件（HRE）的短DNA序列结合，这些短DNA序列靠近或位于氧敏感基因中，如编码促血管生成因子血管内皮生长因子（VEGF）的基因。这刺激了基因表达，并可以部分解释为什么巨噬细胞仅在乳腺癌的无血管、缺氧区域表达丰富的VEGF。它还表明巨噬细胞可用于将HRE调节的治疗基因特异性地递送到缺氧肿瘤区域。最近的一项研究表明，缺氧巨噬细胞积累HIF-2而不是HIF-1，促使人们寻找最佳结合HIF-2的HRE构建体，用于基于巨噬细胞的基因治疗方案。然而，本研究表明，当暴露于体外肿瘤特异性缺氧水平时，人巨噬细胞积累的HIF-1水平高于HIF-2;人肿瘤中的巨噬细胞表达丰富的HIF-1;并且在缺氧条件下，人巨噬细胞样细胞系MonoMac 6中HRE驱动的报告基因构建体的表达与HIF-1的相关性比与HIF-2的上调更密切。总之，这些发现表明，HIF-1可能是巨噬细胞中主要的缺氧诱导转录因子，并且HIF-1调节的构建体可能有效地将缺氧调节的基因治疗巨噬细胞递送至人类肿瘤。版权所有© 2001约翰威利父子有限公司
Large numbers of monocytes extravasate from the blood into human tumours, where they differentiate into macrophages. In both breast and prostate carcinomas, these cells accumulate in areas of low oxygen tension (hypoxia), where they respond to hypoxia with the up‐regulation of one or more hypoxia‐inducible factors (HIFs). These then accumulate in the nucleus and bind to short DNA sequences called hypoxia‐response elements (HREs) near or in such oxygen‐sensitive genes as that encoding the pro‐angiogenic factor vascular endothelial growth factor (VEGF). This stimulates gene expression and could explain why, in part, macrophages express abundant VEGF only in avascular, hypoxic areas of breast carcinomas. It also suggests that macrophages could be used to deliver HRE‐regulated therapeutic genes specifically to hypoxic tumour areas. A recent study suggested that hypoxic macrophages accumulate HIF‐2 rather than HIF‐1, prompting the search for HRE constructs that optimally bind HIF‐2 for use in macrophage‐based gene therapy protocols. However, the present study shows that human macrophages accumulate higher levels of HIF‐1 than HIF‐2 when exposed to tumour‐specific levels of hypoxia in vitro; that macrophages in human tumours express abundant HIF‐1; and that expression from HRE‐driven reporter constructs in the human macrophage‐like cell line MonoMac 6 correlates more closely with HIF‐1 than with HIF‐2 up‐regulation under hypoxia. Taken together, these findings suggest that HIF‐1 may be the major hypoxia‐inducible transcription factor in macrophages and that HIF‐1‐regulated constructs are likely to be effective in macrophage delivery of hypoxia‐regulated gene therapy to human tumours. Copyright © 2001 John Wiley & Sons, Ltd.
影响因子：
11.2
作者：
Janice M. Y. Brown;A. Giaccia
通讯作者：
Janice M. Y. Brown;A. Giaccia
影响因子：
10.5
作者：
Tian, H;McKnight, SL;Russell, DW
通讯作者：
Russell, DW