缺氧(环境)
缺氧诱导因子
生物
转录因子
癌症研究
基因表达
细胞培养
基因
HIF1A型
巨噬细胞
血管生成
免疫学
体外
化学
遗传学
氧气
有机化学
作者
B. F. Burke,Ngai Tang,Kevin P. Corke,Dean Tazzyman,Kurosh Ameri,Michael Wells,Claire E. Lewis
摘要
Abstract 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.
科研通智能强力驱动
Strongly Powered by AbleSci AI