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Chemokine expression is associated with the accumulation of tumour associated macrophages (TAMs) and progression in human colorectal cancer

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Abstract

Chemokines promote tumour progression by enhancing proliferation and modifying the immune response. The purpose of this study was to test the hypothesis that CCL2 monocyte chemotactic protein-1 (MCP-1) contributes to the progression of colorectal cancer by influencing the number and distribution of tumour associated macrophages (TAMs). Chemokine expression was assessed in human colorectal adenocarcinomas by ribonuclease protection assay (RPA). Colonic adenocarcinoma cell lines were used to assess chemokine production by enzyme linked immunosorbant assay (ELISA), and Boyden microchemotaxis assays were performed to determine cell line supernatant monocyte chemotactic activity. CCL2 production was assessed in paraffin embedded tumour samples by immunohistochemistry. Finally, the number of macrophages and their distribution was determined in the same colorectal adenocarcinomas and compared with CCL2 expression and tumour stage. Results showed that CCL2 produced by cell lines induced monocyte chemoattraction, the expression of this chemokine in solid cancers increased with tumour stage (P < 0.05) and immunohistochemistry localized production to tumour cells. Analysis of the macrophage infiltrate showed that the accumulation was significantly greater in tumours than controls (P < 0.005) and within tumours it was greatest in necrotic regions (median 44,600 per mm3). Macrophage accumulation increased with tumour stage and correlated with CCL2 expression (r s = 0.8). CXCL8 interleukin 8 (IL-8), a potent angiogenic factor and growth factor, was expressed in all tumours and cell lines. It is concluded that CCL2 induces the accumulation of tumour promoting TAMs in human colorectal cancer and represents a therapeutic target to modify the macrophage response and direct immune mediated therapy.

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Abbreviations

ATP:

Adenosine triphosphate

DAB:

Diaminobenzidine

ELISA:

Enzyme linked immunosorbant assay

FBS:

Fetal bovine serum

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

IL-8:

Interleukin 8

IP-10:

Interferon inducible protein 10

Ltn:

Lymphotactin

mAb:

Monoclonal antibody

MCP-1:

Monocyte chemotactic protein-1

MIP-1α:

Macrophage inflammatory protein 1 alpha

MIP-1β:

Macrophage inflammatory protein 1 beta

MMP-9:

Matrix metalloproteinase-9

PBS:

Phosphate buffered saline

RANTES:

Regulated on activation normal T-cell expressed and secreted

RPA:

Ribonuclease protection assay

SE:

Standard error

TAM:

Tumour associated macrophage

TBE:

Tris-borate buffer

TNFα:

Tumour necrosis factor α

UTP:

Uridine-5′-triphosphate

VEGF:

Vascular endothelial growth factor

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Acknowledgements

Supported by grants from The Foyle Foundation and The Royal College of Surgeons of England. We are very grateful to Professor F Balkwill and Dr M Grimshaw, Cancer Research UK Translational Oncology Laboratory, London, for their assistance with this work.

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Authors and Affiliations

  1. Department of Surgical Oncology and Technology, St Mary’s Hospital, Imperial College of Science, Technology, and Medicine, London, UK

    Charles Bailey, Alistair Morris, Paul Ziprin, David Peck & Ara Darzi

  2. Department of Colorectal Surgery, Level 2, John Radcliffe Hospital, Oxford, OX3 9DU, UK

    Charles Bailey

  3. Department of Gastroenterology, St Mary’s Hospital, London, UK

    Rupert Negus

  4. Department of Pathology, St Mary’s Hospital, Imperial College of Science, Technology, and Medicine, London, UK

    Robert Goldin

  5. Istituto Clinico Humanitas, 20089, Rozzano, Milan, Italy

    Paola Allavena

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  1. Charles Bailey
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Correspondence to Charles Bailey.

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Bailey, C., Negus, R., Morris, A. et al. Chemokine expression is associated with the accumulation of tumour associated macrophages (TAMs) and progression in human colorectal cancer. Clin Exp Metastasis 24, 121–130 (2007). https://doi.org/10.1007/s10585-007-9060-3

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  • DOI: https://doi.org/10.1007/s10585-007-9060-3

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