Cancer and the chemokine network

Balkwill, Frances R.

doi:10.1038/nrc1388

Cited by 2,109 publications

(1,741 citation statements)

References 80 publications

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“…The biological role of chemokines has two aspects in these processes; the role of chemokines in controlling leukocyte infiltration in cancer, and the influence of chemokines on the metastatic potential and site-specific spread of tumor cells (Balkwill, 2004). It has been demonstrated that CXCL9, CXCL10 and CCL21 exert antitumor activities by inducing immune-stimulating and angiostatic effects (Tannenbaum et al, 1998;Vicari et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, the roles of chemokines in malignant tumors appear complex. Whereas many chemokines show antitumor activities by stimulating immune cells or by inhibiting tumor neovascularization (angiogenesis), other chemokines may promote tumor growth and metastasis by directly stimulating growth, and enhancing cell motility and/or angiogenesis (Balkwill, 2004). Regarding the direct role of chemokines in LN metastasis, recent reports suggest a critical role for chemokine receptors CXCR3 and CCR7 in metastasis of melanoma and breast cancer (Mu¨ller et al, 2001;Robledo et al, 2001;Kawada et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes

et al. 2007

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Chemokines and their receptors are essential for leukocyte trafficking, and also implicated in cancer metastasis to specific organs. We have recently demonstrated that CXCR3 plays a critical role in metastasis of mouse melanoma cells to lymph nodes. Here, we show that some human colon cancer cell lines express CXCR3 constitutively. We constructed cells that expressed CXCR3 cDNA ('DLD-1-CXCR3'), and compared with nonexpressing controls by rectal transplantation in nude mice. Although both cell lines disseminated to lymph nodes at similar frequencies at 2 weeks, DLD-1-CXCR3 expanded more rapidly than the control in 4 weeks. In 6 weeks, 59% of mice inoculated with DLD1-CXCR3 showed macroscopic metastasis in para-aortic lymph nodes, whereas only 14% of those with the control (Po0.05). In contrast, metastasis to the liver or lung was rare, and unaffected by CXCR3 expression. In clinical colon cancer samples, we found expression of CXCR3 in 34% cases, most of which had lymph node metastasis. Importantly, patients with CXCR3-positive cancer showed significantly poorer prognosis than those without CXCR3, or those expressing CXCR4 or CCR7. These results indicate that activation of CXCR3 with its ligands stimulates colon cancer metastasis preferentially to the draining lymph nodes with poorer prognosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes

et al. 2007

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“…CCR4, a seven-transmembrane G-protein-coupled receptor, is expressed on monocytes, T cells, B cells, basophils, NK cells, immature DC and adult T cell leukemia [26][27][28]. CCR4 binds CCL2, -3, -5, -17 and -22 [26,28].…”

Section: Discussionmentioning

confidence: 99%

Migration of cytotoxic T lymphocytes toward melanoma cells in three‐dimensional organotypic culture is dependent on CCL2 and CCR4

et al. 2006

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Studies in experimental animal models have demonstrated that chemokines produced by tumor cells attract chemokine receptor-positive T lymphocytes into the tumor area. However, in cancer patients, the role of chemokines in T lymphocyte trafficking toward human tumor cells is relatively unexplored. In the present study, the migration of a melanoma patient's CTL toward autologous tumor cells has been studied in a novel three-dimensional organotypic melanoma culture. In this model, CTL migrated toward tumor cells, resulting in tumor cell apoptosis. CTL migration was mediated by the CC chemokine receptor (CCR)4 expressed by the CTL and the CC chemokine ligand (CCL)2 secreted by the tumor cells, as evidenced by blockage of CTL migration by CCL2 or antibodies to CCL2 or CCR4. These results were confirmed in a Transwell migration assay in which the CTL actively migrated toward isolated CCL2 and migration was inhibited by anti-CCR4 antibody. These studies, together with previous studies in mice indicating regression of CCL2-transduced tumor cells, suggest that CCL2 may be useful as an immunotherapeutic agent for cancer patients.

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“…To make progress in this area, it is essential to obtain more detailed knowledge of the molecular mechanisms involved in metastasis. Recently, chemokines and their receptors, for example CXCL12 (SDF-1)-CXCR4 biological axis, have been demonstrated to be associated with growth and metastasis of cancer cells (Vicari and Caux, 2002;Balkwill, 2004), in addition to their role in regulating leukocyte trafficking. Many studies suggest that some chemokines such as CXCL8 (IL-8) and CCL2 (MCP-1, MCAF, JE) accelerate tumor growth and metastasis through their enhancement of angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

Enhanced expression of Duffy antigen receptor for chemokines by breast cancer cells attenuates growth and metastasis potential

et al. 2006

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In addition to the role in regulating leukocyte trafficking, chemokines recently have been shown to be involved in cancer growth and metastasis. Chemokine network in tumor neovascularity may be regulated by decoy receptors. Duffy antigen receptor for chemokines (DARC) is a specific decoy receptor binding with the angiogenic CC and CXC chemokines. To investigate the effects of DARC on the tumorigenesis and the metastasis potential of human breast cancer cells, human DARC cDNA was reintroduced into the MDA-MB-231 and MDA-MB-435HM cells which have a high capability of spontaneous pulmonary metastasis. We demonstrated that DARC overexpression induced inhibition of tumorigenesis and/ or metastasis through interfering with the tumor angiogenesis in vivo. This inhibition is associated with decreasing CCL2 protein levels, and MVD and MMP-9 expression in xenograft tumors. In human breast cancer samples, we also demonstrated that low expression of the DARC protein is significantly associated with estrogen receptor (ER) status, MVD, lymph node metastasis, distant metastasis and poor survival. Our results suggest for the first time that DARC is a negative regulator of growth in breast cancer, mainly by sequestration of angiogenic chemokines and subsequent inhibition of tumor neovascularity.

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Cancer and the chemokine network

Cited by 2,109 publications

References 80 publications

Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes

Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes

Migration of cytotoxic T lymphocytes toward melanoma cells in three‐dimensional organotypic culture is dependent on CCL2 and CCR4

Enhanced expression of Duffy antigen receptor for chemokines by breast cancer cells attenuates growth and metastasis potential

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