Journal Article

Cancer and the chemokine network

Balkwill, Fran

2004

Overview

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. 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?

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Animals / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Autoimmune Diseases - drug therapy / Autoimmune Diseases - physiopathology / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Chemokines / Chemokines - antagonists & inhibitors / Chemokines - classification / Chemokines - physiology / Chemotaxis, Leukocyte - physiology / Control / Gene expression / Genetic aspects / Health aspects / Humans / Inflammation - drug therapy / Inflammation - physiopathology / Lymphocytes, Tumor-Infiltrating - physiology / Macrophage Activation - physiology / Mice / Mice, Nude / Models, Biological / Neoplasm Invasiveness - physiopathology / Neoplasm Metastasis - physiopathology / Neoplasm Proteins - physiology / Neoplasms - drug therapy / Neoplasms - immunology / Neoplasms - physiopathology / Receptors, Chemokine - antagonists & inhibitors / Receptors, Chemokine - physiology / review-article / Xenograft Model Antitumor Assays