Expression of HIF-1alpha by human macrophages: implications for the use of macrophages in hypoxia-regulated cancer gene therapy.
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.
Burke
Bernard
B
Tumour Targeting Group, Academic Unit of Pathology, Section of Oncology and Pathology, Division of Genomic Medicine, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK.
Tang
Ngai
N
Corke
Kevin P
KP
Tazzyman
Dean
D
Ameri
Kurosh
K
Wells
Michael
M
Lewis
Claire E
CE
D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D001943:Breast Neoplasms / Q000737:chemistry; D002277:Carcinoma / Q000737:chemistry; D018270:Carcinoma, Ductal, Breast / Q000737:chemistry; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D008156:Luciferases / Q000235:genetics; D008264:Macrophages / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D010051:Ovarian Neoplasms / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000737:chemistry; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000378:metabolism*; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008156:Luciferases; D014157:Transcription Factors; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C497442:HIF1A protein, human