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The CXCL12–CXCR4 chemotactic pathway as a target of adjuvant breast cancer therapies

Nature Reviews Cancer volume 4, pages 901–909 (2004)Cite this article

Abstract

Dose-dense adjuvant breast cancer chemotherapy is a new treatment strategy that aims to improve tumour control by using more frequent cytotoxic dosing together with continuous granulocyte colony-stimulating factor (G-CSF) to minimize neutropaenia. In addition to stimulating neutrophil proliferation, G-CSF mobilizes neutrophils from the bone marrow through proteolytic disruption of the chemokine receptor CXCR4 and its chemotactic ligand CXCL12. As breast cancers also express CXCR4 and oestrogen induces CXCL12, the success of dose-dense treatment could partly reflect inhibition of CXCR4-dependent micrometastatic homing and/or paracrine survival, and suggests a benefit of adjuvant oestrogen suppression for patients with oestrogen-receptor-negative, CXCR4-positive disease.

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Figure 1: Physiology of neutrophil mobilization.
Figure 2: Tissue-homing effects of cell-surface CXCR4 expression in normal and malignant contexts.
Figure 3: Proposed mechanisms for the divergent effects of chemotherapy and/or G-CSF in different transplant (donor cell) and adjuvant therapy (tumour cell) contexts.
Figure 4: Comparison of tumour-centric versus tissue-based models of hormonal action in the adjuvant setting.

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Acknowledgements

Thanks are due to B.S. Mann of the Center for Drug Evaluation and Research, FDA, Rockville, Maryland, USA, and to J.C. Chim from the Division of Haematology/Oncology, Queen Mary Hospital, Hong Kong, for constructive comments on the manuscript.

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  1. the Department of Medicine, The University of Hong Kong, Room 404, Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong

    Richard J. Epstein

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DATABASES

Entrez Gene

AKT

β-catenin

cathepsin G

CXCL12

CXCR4

DPPIV

E-cadherin

ERBB2

FAK

G-CSF

p53

VCAM1

VHL

National Cancer Institute

breast cancer

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Epstein, R. The CXCL12–CXCR4 chemotactic pathway as a target of adjuvant breast cancer therapies. Nat Rev Cancer 4, 901–909 (2004). https://doi.org/10.1038/nrc1473

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