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  • Review Article
  • Published:

The role of myeloid cells in the promotion of tumour angiogenesis

Key Points

  • Bone marrow-derived myeloid cells such as macrophages, neutrophils, eosinophils, mast cells and dendritic cells infiltrate malignant tumours in large numbers and are sometimes a prominent feature in the stroma of such tissues.

  • A wide array of chemoattractants released by both malignant and stromal cells in tumours recruit myeloid cells from the tumour vasculature into tumours.

  • Recent studies have shown these cells not only to be central in the regulation of inflammatory events and various immune mechanisms but also to have an important role in driving various crucial processes in tumorigenesis, including angiogenesis.

  • Their role in tumour progression is often multifaceted and includes the production of pro-angiogenic growth factors and vascular-modulating enzymes. It may also extend to their possible trans-differentiation into endothelial cells in response to prolonged pro-angiogenic stimuli in tumours.

  • Signals produced within the tumour microenvironment appear to stimulate many of the pro-angiogenic functions of these cells. For example, tumour-infiltrating macrophages are stimulated to act as a potent pro-angiogenic force in tumours by exposure to tumour hypoxia and/or such tumour cell-derived cytokines as vascular endothelial growth factor (VEGF), tumour necrosis factor α and angiopoietin 2.

  • Antibodies (and other inhibitors) that block the uptake of pro-angiogenic myeloid cells such as monocytes into tumours are now being developed and tested in preclinical mouse models. For example, a neutralizing antibody to CCL2 markedly reduces both the number of tumour-associated macrophages and tumour angiogenesis.

  • Some subpopulations of myeloid cells inhibit the anti-angiogenic response of tumours to antibodies targeting VEGF and placental growth factor in tumours. They have also been implicated in tumour responses to chemotherapy or radiation therapy.

Abstract

The use of various transgenic mouse models and analysis of human tumour biopsies has shown that bone marrow-derived myeloid cells, such as macrophages, neutrophils, eosinophils, mast cells and dendritic cells, have an important role in regulating the formation and maintenance of blood vessels in tumours. In this Review the evidence for each of these cell types driving tumour angiogenesis is outlined, along with the mechanisms regulating their recruitment and activation by the tumour microenvironment. We also discuss the therapeutic implications of recent findings that specific myeloid cell populations modulate the responses of tumours to agents such as chemotherapy and some anti-angiogenic therapies.

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Figure 1: Origins and expression of cell surface markers by various myeloid cell types present in tumours.
Figure 2: The role of myeloid cells in tumour angiogenesis: the picture to date.

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Acknowledgements

The authors gratefully acknowledge the support of Yorkshire Cancer Research, UK, Cancer Research UK, Breast Cancer Campaign, UK and Prostate Cancer Campaign, UK for their work in this area. They also thank S. Ostrand-Rosenberg for her helpful advice on the MDSC section. M.M. is the recipient of the 2008 BACR–AstraZeneca Young Scientist Frank Rose Award. We apologize to any investigators whose papers could not be cited owing to space limitations.

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DATABASES

National Cancer Institute

bladder cancer

breast cancer

colon cancer

endometrial cancer

Hodgkin lymphoma

kidney cancer

lung cancer

melanoma

multiple myeloma

oral cavity

oesophagael cancer

ovarian cancer

pancreatic tumours

stomach cancer

National Cancer Institute Drug Dictionary

cyclophosphamide

ganciclovir

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Glossary

T-helper-1 cell response

(TH1 response). A TH1 immune response is mediated by pro-inflammatory cytokines such as IFNγ, IL1β and TNFα. It promotes cellular immune responses against intracellular infections and malignancy.

T-helper-2 cell response

(TH2 response). A TH2 response involves production of cytokines, such as IL4, that stimulate antibody production. TH2 cytokines promote secretory immune responses of mucosal surfaces to extracellular pathogens and allergic reactions.

Clodronate liposomes

Liposomes encapsulating the agent clodronate. Monocytes and macrophages readily engulf these structures by endocytosis. The lipid bilayer is then broken down by phospholipases in lysosomes and clodronate is released into the cell where it then induces apoptosis in the host cell.

Gene-directed enzyme–pro-drug therapy

Delivery of a gene encoding a non-mammalian enzyme into a specific cell population. The enzyme converts a systemically delivered pro-drug into an active cytotoxic agent only in the cells that express the enzyme.

Endocrine-gland-derived VEGF

EG-VEGF, also known as prokineticin 1 (PK1), is a cytokine that resembles VEGF in that it promotes angiogenesis and vascular permeability; the two proteins are structurally dissimilar and work through different receptors.

Rat aortic ring assay

An organ culture assay in which a rat aorta is cut into segments before being placed in a matrix such as Matrigel or a collagen gel. The explants are monitored for the outgrowth of vessel-like extensions from the aorta.

CAM assay

An angiogenesis assay in which the shell of a fertilized chick egg is cut open and the embryo with intact chorioallantoic membrane (CAM) incubated in a Petri dish until blood vessels in the CAM become visible. Test substances or cells are then placed on the membrane and their effects on vessel formation in the CAM examined by microscopy.

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Murdoch, C., Muthana, M., Coffelt, S. et al. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer 8, 618–631 (2008). https://doi.org/10.1038/nrc2444

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