Chemokine biology in cancer
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
References (56)
- et al.
Inflammation and cancer: back to Virchow
Lancet
(2001) - et al.
The role of cytokines in classical Hodgkin lymphoma
Blood
(2002) - et al.
The viral chemokine macrophage inflammatory protein-II is a selective Th2 chemoattractant
Blood
(1998) Tumor necrosis factor or tumor promoting factor?
Cytokine Growth Factor Rev.
(2002)- et al.
The origin and function of tumor-associated macrophages
Immunol. Today
(1992) - et al.
The role of Mig, the monokine induced by interferon-gamma, and IP-10, the interferon-gamma-inducible protein-10, in tissue necrosis and vascular damage associated with Epstein-Barr virus-positive lymphoproliferative disease
Blood
(1997) - et al.
Chemokines in cancer
Cytokine Growth Factor Rev.
(2002) Chemokines and molecular basis of cancer metastasis
New Engl. J. Med.
(2001)- et al.
Role of CXCL1 in tumorigenesis of melanoma
J. Leukoc. Biol.
(2002) - et al.
Tumors and inflammatory infiltrates: friends or foes?
Clin. Exp. Metastasis
(2002)
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
Clin. Cancer Res.
Analysis of CC chemokine and chemokine receptor expression in solid ovarian tumours
Br. J. Cancer
Defective expression of the monocyte chemotactic protein-1 receptor CCR2 in macrophages associated with uman ovarian carcinoma
J. Immunol.
Inhibition of monocyte and macrophage chemotaxis by hypoxia and inflammation—a potential mechanism
Eur. J. Immunol.
Autocrine production of IL-10 mediates defective IL-12 production and NF-k activation in tumor-associated macrophages
J. Immunol.
Control of TH2 polarization by the chemokine monocyte chemoattractant protein-1
Nature
Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells
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.
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