Cited by 413Immune cells in cancerCancer, Hypoxia, and MetabolismAngiogenesis and VEGF in Cancer

Macrophage Responses to Hypoxia

Open access
Lewis, Claire, Murdoch, Craig·2005·The American Journal of Pathology

Abstract

The presence of multiple areas of hypoxia (low oxygen tension) is a hallmark feature of human and experimental tumors. Monocytes are continually recruited into tumors, differentiate into tumor-associated macrophages (TAMs), and then accumulate in these hypoxic areas. A number of recent studies have shown that macrophages respond to the levels of hypoxia found in tumors by up-regulating such transcription factors as hypoxia-inducible factors 1 and 2, which in turn activate a broad array of mitogenic, pro-invasive, pro-angiogenic, and pro-metastatic genes. This could explain why high numbers of TAMs correlate with poor prognosis in various forms of cancer. In this review, we assess the evidence for hypoxia activating a distinct, pro-tumor phenotype in macrophages and the possible effect of this on the growth, invasion, angiogenesis, and immune evasion of tumors. We also discuss current attempts to selectively target TAMs for destruction or to use them to deliver gene therapy specifically to hypoxic tumor sites.

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  • Macrophages accumulate in hypoxic environments to release prohealing and pro-angiogenic factors such as VEGF, PDGF and enzymes such as COX2.

    “Macrophages accumulate in hypoxic environments to release prohealing and pro-angiogenic factors such as vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF) [63] and enzymes such as Cyclooxygenase 2 (COX2) [64].”

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5 of the 155 references couldn’t be matched to a known paper.

Research works printed but not linked: 9

  1. Bingle L, Brown NJ, Lewis CE: The role of tumor-associated macro- phages in tumor progression: implications for new anticancer thera- pies. J Pathol 2002, 196:254 -265
  2. Konur A, Kreutz M, Knuchel R, Krause SW, Andressen R: Three dimensional co-culture of human monocytes and macrophages with tumor cells: analysis of macrophage differentiation and activation. Int J Cancer 1996, 66:645-652
  3. Shannon AM, Bouchier-Hayes DJ, Condron CM, Toomey D: Tumor hypoxia, chemotherapeutic resistance and hypoxia-related thera- pies. Cancer Treat Rev 2003, 29:297-307
  4. Grimshaw MJ, Balkwill FR: Inhibition of monocyte and macrophage chemotaxis by hypoxia and inflammation-a potential mechanism. Eur J Immunol 2001, 31:480 -489
  5. Kong T, Eltzschig HK, Karhausen J, Colgan SP, Shelley CS: Leuko- cyte adhesion during hypoxia is mediated by HIF-1-dependent in- duction of beta2 integrin gene expression. Proc Natl Acad Sci USA 2004, 101:10440 -10445
  6. Lewis JS, Landers RJ, Underwood JC, Harris AL, Lewis CE: Expres- sion of vascular endothelial growth factor by macrophages is up- regulated in poorly vascularized areas of breast carcinomas. J Pathol 2000, 192:150 -158
  7. Grimshaw MJ, Wilson JL, Balkwill FR: Endothelin-2 is a macrophage chemoattractant: implications for macrophage distribution in tumors. Eur J Immunol 2002, 32:2393-2400
  8. Murata Y, Ohteki T, Koyasu S, Hamuro J: IFN-gamma and pro- inflammatory cytokine production by antigen-presenting cells is dic- tated by intracellular thiol redox status regulated by oxygen tension. Eur J Immunol 2002, 32:2866 -2873
  9. Ohno S, Ohno Y, Suzuki N, Kamei T, Koike K, Inagawa H, Kohchi C, Soma G, Inoue M: Correlation of histological localization of tumor- associated macrophages with clinicopathological features in endo- metrial cancer. Anticancer Res 2004, 24:3335-3342

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Authors
Lewis, C., & Murdoch, C.
Affiliations
University of Sheffield (GB)
Corresponding author
Lewis, Claire
Venue
The American Journal of Pathology
Publisher
Elsevier BV
Published
2005-09
Volume
167
Issue
3
Pages
627-635
ISSN
0002-9440 (ISSN-L)
OpenAlex
W1515730558
Cited by
413
References
155
Citations by year
2026: 2 · 2025: 10 · 2024: 12 · 2023: 16 · 2022: 15 · 2021: 16 · 2020: 19 · 2019: 21 · 2018: 13 · 2017: 25 · 2016: 19 · 2015: 17 · 2014: 26 · 2013: 20 · 2012: 27
FWCI
1.97
Type
journal article
Language
en
Open access
Locations
  • American Journal Of Pathology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Wellcome Trust
  • School of Medicine, University of North Carolina at Chapel Hill
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Keywords
tumor-associated macrophages, hypoxia, HIF-1, HIF-2, tumor microenvironment, tumor invasion, tumor angiogenesis, metastasis, immune evasion, macrophage polarization, TAM-targeted therapy
MeSH terms
Animals, Hypoxia, Humans, Macrophages, Neoplasms, Disease Progression

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