Regulation of macrophage production of vascular endothelial growth factor (VEGF) by hypoxia and transforming growth factor β-1

被引:184
作者
Harmey, JH [1 ]
Dimitriadis, E
Kay, E
Redmond, HP
Bouchier-Hayes, D
机构
[1] Beaumont Hosp, Dept Surg, Royal Coll Surg Ireland, Dublin 9, Ireland
[2] Beaumont Hosp, Dept Pathol, Royal Coll Surg Ireland, Dublin 9, Ireland
关键词
vascular endothelial growth factor; human macrophage; hypoxia; breast cancer;
D O I
10.1007/BF02303785
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: Breast tumors contain high numbers of infiltrating macrophages. The role and function of these cells within the tumor remain unclear, but a number of studies have found an association between poor prognosis and macrophage content in human breast cancer. Both hypoxia and TGF beta-1 have been shown to regulate VEGF in other cell types. We hypothesized that bn:ast tumor-associated macrophages produce VEGF and that macrophage production of this factor is regulated by both hypoxia and TGF beta-1. Methods: Paraffin-embedded breast tumor sections were stained immunohistochemically viith anti-VEGF, anti-CD68, and anti-cytokeratin. Monocytes were matured for 3 days in 20% autologous plasma and activated with 1000 U/mL interferon-gamma for 24 hours. Supernatants were assayed for VEGF protein by ELISA. Total RNA was isolated from cells and reverse transcribed to cDNA which was used as a template in PCR reactions for VEGF and beta-actin. Results: Both tumor cells and tumor macrophages produce VEGF in human breast tumors. Hypoxia increases VEGF protein and mRNA levels in monocyte-derived macrophages, whereas TGF beta-1 increases VEGF protein but not mRNA under hypoxic growth conditions. Conclusions: Breast tumor-associated macrophages may contribute to the angiogenic activity of human breast tumors by producing VEGF. Macrophage production of VEGF is upregulated by hypoxia and TGF beta-1, both of which occur in the tumor environment. Macrophage production of VEGF is regulated at both the mRNA and protein levels.
引用
收藏
页码:271 / 278
页数:8
相关论文
共 28 条
  • [1] VASCULAR-PERMEABILITY FACTOR (VASCULAR ENDOTHELIAL GROWTH-FACTOR) GENE IS EXPRESSED DIFFERENTIALLY IN NORMAL-TISSUES, MACROPHAGES, AND TUMORS
    BERSE, B
    BROWN, LF
    VANDEWATER, L
    DVORAK, HF
    SENGER, DR
    [J]. MOLECULAR BIOLOGY OF THE CELL, 1992, 3 (02) : 211 - 220
  • [2] INDIRECT ANGIOGENIC CYTOKINES UP-REGULATE VEGF AND BFGF GENE-EXPRESSION IN VASCULAR SMOOTH-MUSCLE CELLS, WHEREAS HYPOXIA UP-REGULATES VEGF EXPRESSION ONLY
    BROGI, E
    WU, TG
    NAMIKI, A
    ISNER, JM
    [J]. CIRCULATION, 1994, 90 (02) : 649 - 652
  • [3] EXPRESSION OF VASCULAR-PERMEABILITY FACTOR (VASCULAR ENDOTHELIAL GROWTH-FACTOR) BY EPIDERMAL-KERATINOCYTES DURING WOUND-HEALING
    BROWN, LF
    YEO, KT
    BERSE, B
    YEO, TK
    SENGER, DR
    DVORAK, HF
    VANDEWATER, L
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 1992, 176 (05) : 1375 - 1379
  • [4] VASCULAR-PERMEABILITY FACTOR - A TUMOR-DERIVED POLYPEPTIDE THAT INDUCES ENDOTHELIAL-CELL AND MONOCYTE PROCOAGULANT ACTIVITY, AND PROMOTES MONOCYTE MIGRATION
    CLAUSS, M
    GERLACH, M
    GERLACH, H
    BRETT, J
    WANG, F
    FAMILLETTI, PC
    PAN, YCE
    OLANDER, JV
    CONNOLLY, DT
    STERN, D
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 1990, 172 (06) : 1535 - 1545
  • [5] TGF beta-1 regulation of VEGF production by breast cancer cells
    Donovan, D
    Harmey, JH
    Toomey, D
    Osborne, DH
    Redmond, HP
    BouchierHayes, DJ
    [J]. ANNALS OF SURGICAL ONCOLOGY, 1997, 4 (08) : 621 - 627
  • [6] DOUGHERTY GJ, 1989, MONOCYTE DIFFERENTIA, P49
  • [7] DVORAK HF, 1995, AM J PATHOL, V146, P1029
  • [8] TUMOR DORMANCY IN-VIVO BY PREVENTION OF NEOVASCULARIZATION
    GIMBRONE, MA
    COTRAN, RS
    FOLKMAN, J
    LEAPMAN, SB
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 1972, 136 (02) : 261 - &
  • [9] THE VASCULAR ENDOTHELIAL GROWTH-FACTOR FAMILY - IDENTIFICATION OF A 4TH MOLECULAR-SPECIES AND CHARACTERIZATION OF ALTERNATIVE SPLICING OF RNA
    HOUCK, KA
    FERRARA, N
    WINER, J
    CACHIANES, G
    LI, B
    LEUNG, DW
    [J]. MOLECULAR ENDOCRINOLOGY, 1991, 5 (12) : 1806 - 1814
  • [10] KNIGHTON DR, 1983, SCIENCE, V221, P1284