Chemokine biology in cancer

doi:10.1016/S1044-5323(02)00127-6

Seminars in Immunology

Volume 15, Issue 1, February 2003, Pages 49-55

https://doi.org/10.1016/S1044-5323(02)00127-6 Get rights and content

Abstract

Many human cancers possess a complex chemokine network that may influence the extent and phenotype of the leukocyte infiltrate, angiogenesis, tumor cell growth, survival and migration. Restricted expression of chemokine receptors on leukocytes may allow concise control of cell movement and retention at the tumor site. Restricted and specific expression of chemokine receptors on tumor cells may be involved in the characteristic patterns of metastasis , and may promote tumor cell growth and survival. Detailed study of chemokine and chemokine receptor antagonists in experimental cancer models is warranted. Manipulation of the tumor chemokine network could have therapeutic potential in malignant disease.

Introduction

Many cancers express an extensive network of chemokines and chemokine receptors [1], [2], [3]. These tumors are characterized by disregulated production of chemokines and abnormal chemokine receptor signaling and expression [4], [5]. Tumor-associated chemokines are thought to play at least five roles in the biology of primary and metastatic disease: control of the leukocyte infiltrate into the tumor; manipulation of tumor immune response; regulation of angiogenesis; action as autocrine or paracrine growth and survival factors; and control of the movement of tumor cells themselves. All the evidence published so far indicates that these biological activities of chemokines in the tumor microenvironment are more likely to contribute to cancer growth and spread than to any host anti-tumor response. This article will summarize current information on these five areas and discuss how this could be exploited in novel biological therapies of cancer.

Section snippets

Chemokines may control the leukocyte infiltrate in cancers

Most solid tumors, be they of epithelial, mesothelial or haemopoietic origin, comprise a mixture of malignant and stromal cells. Stromal cells are recruited into the tumor tissue and are integral to growth of primary tumor and spread of metastases [6], [7], [8]. The predominant stromal cells found in cancers are macrophages, lymphocytes, endothelial cells and fibroblasts, with eosinophils, granulocytes, natural killer cells and B cells also reported in some tumor types.

Chemokines contribute to immune suppression in tumors

Infiltrating leukocytes may not only contribute to tumor progression by producing MMPs and growth, angiogenic and immunosuppressive factors, but the profile of the cells attracted by chemokines to the tumor may contribute to an immunosuppressive environment. There is often a prevalence of Th2 cells in tumors and this polarization may be a general strategy to subvert immune responses against tumors [2]. Hodgkin’s disease, for instance, is characterized by constitutive activation of NFκB and

A balance of angiogenic and angiostatic chemokines exists in tumors

Chemokines may also regulate angiogenesis in the epithelial tumor microenvironment. CXC chemokines containing the three amino acid (ELR) motif glutamine-leucine-arginine, such as CXCL8 (IL-8), CXCL1, CXCL5 (ENA-78), CXCL6 (GCP-2), and CXCL7 (NAP-2), promote angiogenesis [22]. They are directly chemotactic for endothelial cells and can stimulate angiogenesis in neo-vascularization experiments in vivo. Elevated levels of CXCL5 were found, for instance, in primary non-small cell lung cancer,

Chemokines and tumor cell growth

As well as promoting angiogenesis, deregulated chemokines may contribute directly to transformation of tumor cells by acting as growth and survival factors, generally in an autocrine manner. This action of chemokines has been extensively characterized in malignant melanoma. CXCL1 and CXCL8 are constitutively produced by melanoma cells, but not by untransformed melanocytes [1], [4], [24]. Melanoma cells also show elevated levels of the CXCR2 receptor for these chemokines, and autocrine chemokine

Malignant cells may respond to chemokine gradients

Chemokines are central to the normal and pathologic trafficking of leukocytes and it seems that mechanisms utilized in homing of leukocytes may also be used by tumor cells. Restricted and specific expression of chemokine receptors, especially CXCR4 and CCR7, by tumor cells, may be one important step in the development of site specific metastasis. For example, tumor cells from breast, prostate, pancreatic, gastric and ovarian carcinomas, neuroblastoma, glioblastoma, melanoma and some leukaemias,

Manipulation of the chemokine network in tumors

There are a number of areas where inactivation of chemokines and their receptors could be therapeutic in cancer. A change in the extent and composition of the leukocyte infiltrate could inhibit angiogenesis, survival and spread of tumor cells. Manipulation of some tumor chemokines could also directly affect angiogenesis. Direct inhibition of the action of tumor cell chemokine receptors may prevent or delay lymph node and haematogenous metastases and may decrease survival of tumor cells at the

Concluding remarks

The chemokine network in human tumors is complex and its role is only partially understood. There is a great deal of information on potential roles of individual chemokines, but more work is needed to define the overall chemokine and chemokine receptor profile of individual tumor types, and the cells within them. The chemokines that are produced by human tumors are part of an even more complex network of inflammatory, immunomodulating and growth promoting cytokines, and little is known about

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Chemokine biology in cancer

Abstract

Introduction

Section snippets

Chemokines may control the leukocyte infiltrate in cancers

Chemokines contribute to immune suppression in tumors

A balance of angiogenic and angiostatic chemokines exists in tumors

Chemokines and tumor cell growth

Malignant cells may respond to chemokine gradients

Manipulation of the chemokine network in tumors

Concluding remarks

Lancet

Blood

Blood

Cytokine Growth Factor Rev.

Immunol. Today

Blood

Chemokines in cancer

Cytokine Growth Factor Rev.

Chemokines and molecular basis of cancer metastasis

New Engl. J. Med.

Role of CXCL1 in tumorigenesis of melanoma

J. Leukoc. Biol.

Tumors and inflammatory infiltrates: friends or foes?

Clin. Exp. Metastasis

Inflammatory cells and cancer: think different!

J. Exp. Med.

A quantitative assessment of the leukocyte infiltrate in ovarian cancer and its relationship to the expression of C-C chemokines

Am. J. Pathol.

Regulation of the macrophage content of neoplasms by chemoattractants

Science

Elevated expression of the CC chemokine regulated on activation, normal T cell expressed and secreted (RANTES) in advanced breast carcinoma

Cancer Res.

Significant correlation of monocyte chemoattractant protein-1 expression with neovascularization and progression of breast carcinoma

Cancer

The CC chemokine RANTES in breast carcinoma progression: regulation of expression and potential mechansisms of promalignant activity

Cancer Res.

The detection and localization of monocyte chemoattractant protein-1 (MCP-1) in human ovarian cancer

J. Clin. Invest.

Analysis of chemokines and chemokine receptor expression in ovarian cancer ascites

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Analysis of CC chemokine and chemokine receptor expression in solid ovarian tumours

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Defective expression of the monocyte chemotactic protein-1 receptor CCR2 in macrophages associated with uman ovarian carcinoma

J. Immunol.

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Autocrine production of IL-10 mediates defective IL-12 production and NF-k activation in tumor-associated macrophages

J. Immunol.

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Nature

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Nature Med.

CXC chemokines in angiogenesis

J. Leukoc. Biol.

Epithelial-neutrophil activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer

J. Clin. Invest.

IL-8 produced by human malignant melanoma cells in vitro is an essential autocrine growth factor

J. Immunol.

Mechanism and biological significance on constitutive expression of MGSA/GRO chemokines in malignant melanoma tumor progression

J. Leukoc. Biol.