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Cancer and the chemokine network

Nature Reviews Cancer volume 4, pages 540–550 (2004)Cite this article

Key Points

  • Chemokines are a subset of cytokines that cause the directed migration of leukocytes along a chemical gradient of ligand, known as the chemokine gradient. More than 50 human chemokines and 18 chemokine receptors have been discovered so far.

  • Many cancers have a complex chemokine network that influences the immune-cell infiltration of a tumour, as well as tumour cell growth, survival and migration, and angiogenesis.

  • Immune cells, endothelial cells and tumour cells themselves express chemokine receptors and can respond to chemokine gradients.

  • Chemokines are a key determinant of the macrophage and lymphocyte infiltrate of human cancers and might contribute to T-helper 2 cell polarization.

  • Malignant cells from different cancer types have different profiles of chemokine-receptor expression, but CXCR4 is most commonly found; at the last count, cells from 23 different cancer types expressed this receptor.

  • Mutations in genes that alter levels of hypoxia-inducible factor, or gene-fusion events, can induce CXCR4 in cells that do not normally express this receptor. CXCR4 is also transiently increased by factors such as hypoxia, vascular endothelial growth factor and oestrogen in the tumour microenvironment.

  • Studies of human cancer biopsy sampler and mouse cancer models show that cancer cell chemokine-receptor expression is associated with increased metastatic capacity.

  • Preliminary laboratory data show that chemokine-receptor antagonists inhibit macrophage infiltrates, can induce tumour growth arrest or apoptosis, and prevent metastatic spread.

  • Research into the cancer chemokine network is revealing parallels between the pathology of inflammation and malignancy, parallels that enhance our understanding of both types of disease and indicate new approaches for treatment.

Abstract

A complex network of chemokines and their receptors influences the development of primary tumours and metastases. New information about the biological role of chemokines in these processes is providing insights into host–tumour interactions, such as the role of the leukocyte infiltrate, and into the mechanisms that determine the metastatic potential and site-specific spread of cancer cells. Chemokine-receptor antagonists are showing promise in animal models of inflammation and autoimmune disease. Could manipulating the local chemokine network have therapeutic benefits in malignant disease?

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Figure 1: Diagram of a chemokine gradient in a cancer.
Figure 2: The chemokine wheel.
Figure 3: The chemokine network of human epithelial ovarian cancer.
Figure 4: The significance of chemokine-receptor expression on cancer cells.

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Acknowledgements

The author wishes to thank J. Wilson, H. Kulbe and V. Slettenaar for stimulating discussion.

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  1. Cancer Research UK Translational Oncology Laboratory, Barts and The London, Queen Mary's Medical School, Charterhouse Square, London, EC1M 6BQ, UK

    Fran Balkwill

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Fran Balkwill is a consultant for Centocor Inc. — the manufacturer of Infliximab (an anti-TNF antibody), which is used in the treatment of inflammatory disease.

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DATABASES

Cancer.gov

breast cancer

chronic lymphocytic leukaemia

epithelial ovarian cancer

Hodgkin's lymphoma

Kaposi's sarcoma

neuroblastoma

non-small-cell lung cancer

pancreatic cancer

prostate cancer

renal-cell carcinoma

thyroid cancer

Entrez Gene

CCL2

CCL3

CCL4

CCL5

CCL8

CCL18

CCL20

CCL21

CCL22

CCR1

CCR6

CCR9

CDKN1A

CXCL1

CXCL2

CXCL8

CXCL12

CX3CR1

CXCR4

CXCR5

CXCR6

IL-10

MDM2

MMP9

VEGF

VHL

Glossary

CHEMOKINE

This term refers to a family of chemotactic cytokines. These small, inducible cytokines are leukocyte-subtype-selective chemoattractants. Some chemokines also have other cytokine-like actions on cells including stimulation of cell proliferation.

HYPOXIA

This term describes the low levels of oxygen that are found in many areas of advanced cancers and are associated with a poor prognosis.

ASCITES

An increased accumulation of fluid in the peritoneum owing to cancer, which both increases the accumulation of peritoneal fluid and inhibits its reabsorption. In some cancers, such as ovarian cancer, the ascitic fluid contains variable numbers of tumour cells and inflammatory leuokytes, as well as pico- to nanomolar levels of many cytokines and chemokines.

CD8+ T LYMPHOCYTE

A T cell bearing the CD8+ cell-surface glycoprotein, which recognizes major histocompatibility complex class I molecules on target cells. CD8+ T cells are usually cytotoxic T cells.

REED–STERNBERG CELLS

A clonal population of transformed germinal-centre B cells that forms the malignant component in Hodgkin's lymphoma.

TH2 CELLS

T-helper 2 (TH2) lymphocytes help B cells make antibody and suppress the action of cytotoxic T cells. Interleukin (IL)-4, IL-5, IL-10 and IL-13 are examples of TH2-produced cytokines.

TH1 CELLS

T-helper 1 (TH1) lymphocytes are at the other end of the functional spectrum to TH2 lymphocytes. They activate macrophages, produce TH1 cytokines — such as interferon-γ and interleukin 2 — and help in the production of specific cytotoxic T lymphocytes.

TYPE-2 MACROPHAGES

Also known as M2 macrophages. Type-2 macrophages have an important role in inflammatory circuits that promote tumour growth and progression. They are polarized cells that are induced by TH2 cytokines and make immunosuppressive cytokines, such as interleukin-10.

ANTIGEN-PRESENTING CELLS

(APCs). Cells that posses antigen and present antigen fragments to lymphocytes in order to initiate an immune response. Dendritic cells are the most potent APCs.

MATRIX METALLOPROTEINASES

A family of proteolytic enzymes that degrade the extracellular matrix and have important roles in tissue remodelling and tumour metastasis.

PROLIFERATIVE INDEX

Describes the numbers of cells that are proliferating in a tissue. Measured by staining cells with antibodies such as Ki67.

AUTOCRINE

A form of bioregulation in which a secretory factor affects the cell from which it was secreted.

RHABDOMYOSARCOMA

A highly lethal mesenchymal cancer of early childhood, which is most commonly found in the eye, head and neck region, and the genitourinary tract.

SCID

Severe combined immunodeficiency. Mice with this defect do not make T cell or antibody responses. Tumour cells from another species can be grown in these mice without rejection.

LEUKOCYTOSIS

The state of increased numbers of leukocytes circulating in the peripheral blood.

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Balkwill, F. Cancer and the chemokine network. Nat Rev Cancer 4, 540–550 (2004). https://doi.org/10.1038/nrc1388

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