Involvement of chemokine receptors in breast cancer metastasis

Müller, Anja; Homey, Bernhard; Soto, Hortensia; Ge, Nianfeng; Catron, Daniel; Buchanan, Matthew E.; McClanahan, Terri; Murphy, Erin; Yuan, Wei; Wagner, Stephan N.; Barrera, José Luís; Mohar, Alejandro; Verástegui, Emma; Zlotnik, Albert

doi:10.1038/35065016

Cited by 4,751 publications

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“…YB-1 as an Akt-regulated gene in ovarian cancer Y Basaki et al the development of tumor growth, angiogenesis and metastasis not only in ovarian cancer (Scotton et al, 2002) but also in other tumor types including breast cancer (Muller et al, 2001), melanoma (Robledo et al, 2001;Murakami et al, 2002) and prostate cancer (Darash-Yahana et al, 2004). Jiang et al (2006) further demonstrated that CXCR4 expression could be an important prognostic marker for ovarian cancers: the rate of CXCR4 expression in refractory and recurrent group was significantly higher than that in nonrecurrent group.…”

Section: Discussionmentioning

confidence: 99%

Akt-dependent nuclear localization of Y-box-binding protein 1 in acquisition of malignant characteristics by human ovarian cancer cells

et al. 2006

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Y-box-binding protein 1 (YB-1), which is a member of the DNA-binding protein family containing a cold-shock domain, has pleiotropic functions in response to various environmental stimuli. As we previously showed that YB-1 is a global marker of multidrug resistance in ovarian cancer and other tumor types. To identify YB-1-regulated genes in ovarian cancers, we investigated the expression profile of YB-1 small-interfering RNA (siRNA)-transfected ovarian cancer cells using a high-density oligonucleotide array. YB-1 knockdown by siRNA upregulated 344 genes, including MDR1, thymidylate synthetase, S100 calcium binding protein and cyclin B, and downregulated 534 genes, including CXCR4, N-myc downstream regulated gene 1, E-cadherin and phospholipase C. Exogenous serum addition stimulated YB-1 translocation from the cytoplasm to the nucleus, and treatment with Akt inhibitors as well as Akt siRNA and integrin-linked kinase (ILK) siRNA specifically blocked YB-1 nuclear localization. Inhibition of Akt activation downregulated CXCR4 and upregulated MDR1 (ABCB1) gene expression. Administration of Akt inhibitor resulted in decrease in nuclear YB-1-positive cancer cells in a xenograft animal model. Akt activation thus regulates the nuclear translocation of YB-1, affecting the expression of drug-resistance genes and other genes associated with the malignant characteristics in ovarian cancer cells. Therefore, the Akt pathway could be a novel target of disrupting the nuclear translocation of YB-1 that has important implications for further development of therapeutic strategy against ovarian cancers.

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Section: Discussionmentioning

confidence: 99%

Akt-dependent nuclear localization of Y-box-binding protein 1 in acquisition of malignant characteristics by human ovarian cancer cells

et al. 2006

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“…It was also reported that Caco 2 metastasized to LNs at a low frequency (1/10) with a cecal CXCR3 in colon cancer metastasis to lymph nodes K Kawada et al transplantation model (Flatmark et al, 2004). Recent studies showed that CCR7 was involved in LN metastasis in breast and stomach cancers, and melanoma (Mu¨ller et al, 2001;Wiley et al, 2001;Mashino et al, 2002). Among the colon cancer cell lines tested by RT-PCR and flow cytometry, however, we found expression of CCR7 only in SW480 and Caco2 that rarely metastasized to LNs (Figure 1b and c).…”

Section: Expression Of Chemokine Receptors Cxcr3 Cxcr4 and Ccr7 In Cmentioning

confidence: 96%

“…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%

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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“…[1][2][3] Monocyte chemotactic protein-1 (MCP-1) or CCL2 is a CC-chemokine that specifically attracts monocytes and memory T cells. It has been particularly implicated in processes characterized by mononuclear cell infiltration including breast cancer.…”

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confidence: 99%

Transactivation of MCP‐1/CCL2 by β‐catenin/TCF‐4 in human breast cancer cells

Mestdagt

Polette

Butticè

et al. 2005

Intl Journal of Cancer

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The loss of E-cadherin expression and the translocation of b-catenin to the nucleus are frequently associated with the metastatic conversion of epithelial cells. In the nucleus, b-catenin binds to the TCF/LEF-1 (T-cell factor/ lymphoid enhancer factor) transcription factor family resulting in the activation of several genes, some of them having important implications in tumour progression. In our study, we investigated the potential regulation of monocyte chemotactic protein-1 (MCP-1/CCL2) expression by the b-catenin/TCF pathway. This CC-chemokine has been implicated in tumour progression events such as angiogenesis or tumour associated macrophage (TAM) infiltration. We thus demonstrated that MCP-1 expression correlates with the reorganization of the E-cadherin/b-catenin complexes. Indeed, MCP-1 was expressed by invasive breast cancer cells (MDA-MB-231, BT549 and Hs578T), which do not express E-cadherin but was not produced by noninvasive breast cancer cell lines (MCF7 and T47D) expressing high level of E-cadherin. In addition, the MCP-1 promoter was activated in BT549 breast cancer cells transfected with b-catenin and TCF-4 cDNAs. The MCP-1 mRNA level was similarly upregulated. Moreover, we showed that MCP-1 mRNA was downregulated after transfection with a siRNA against b-catenin in both BT549 and Hs578T cells. Our results therefore identify MCP-1 as a target of the b-catenin/TCF/LEF pathway in breast tumour cells, a regulation which could play a key role in breast tumour progression. ' 2005 Wiley-Liss, Inc.Key words: MCP-1; b-catenin; breast cancer Chemokines constitute a superfamily of proinflammatory cytokines that are implicated in tumour progression, modulating not only host tumour-specific immunological response but also angiogenesis or tumour cell invasion and proliferation. 1-3 Monocyte chemotactic protein-1 (MCP-1) or CCL2 is a CC-chemokine that specifically attracts monocytes and memory T cells. It has been particularly implicated in processes characterized by mononuclear cell infiltration including breast cancer. 4,5 In some models, MCP-1 has been shown to display an antitumoral effect. 6,7 Nevertheless, a large number of studies demonstrate that MCP-1 facilitates tumour progression through its ability to recruit stromal cells including tumour associated macrophages (TAMs) and endothelial cells. 7-10 A pro-angiogenic role of MCP-1 has been demonstrated in many systems, facilitating tumour growth and dissemination. 8,9,11,12 Moreover, a direct effect of MCP-1 on tumour cell migration in vitro has also been described. 13 Recently, Lebrecht et al. 14 have correlated an increased MCP-1 serum level with an advanced breast tumour stage and the presence of lymph node metastasis. In the same way, Amann et al. 15 reported a significant association between MCP-1 urinary levels and tumour stage and grade. They suggested a use of its urinary level as prognosis marker in bladder cancer. The correlation between MCP-1 expression and a poor prognosis was also demonstrated for the squamous cell carcinoma of the oeso...

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Involvement of chemokine receptors in breast cancer metastasis

Cited by 4,751 publications

References 34 publications

Akt-dependent nuclear localization of Y-box-binding protein 1 in acquisition of malignant characteristics by human ovarian cancer cells

Akt-dependent nuclear localization of Y-box-binding protein 1 in acquisition of malignant characteristics by human ovarian cancer cells

Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes

Transactivation of MCP‐1/CCL2 by β‐catenin/TCF‐4 in human breast cancer cells

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