Expression of Functional Chemokine Receptors CXCR3 and CXCR4 on Human Melanoma Cells

Robledo, Mar M.; Bartolomé, Rubén A.; Longo, Natividad; Rodrı́guez-Frade, José Miguel; Mellado, Mario; Longo, Isabel; Muijen, G.N.P. van; Sánchez‐Mateos, Paloma; Teixidó, Joaquı́n

doi:10.1074/jbc.m106912200

Cited by 218 publications

(201 citation statements)

References 56 publications

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“…Notably, CXCL9, CXCL10 and CCL21 play additional roles in the tumor microenvironment. For example, CXCL9 and CXCL10 activate RhoA and Rac1, induce actin reorganization, and trigger migration and invasion of melanoma, malignant B-lymphocyte, and lung and breast cancers (Trentin et al, 1999;Robledo et al, 2001;Soejima and Rollins, 2001;Kawada et al, 2004;Walser et al, 2006). Here, we have demonstrated that CXCR3 plays a critical role in colon cancer cell metastasis to LNs by inducing diverse cellular effects such as cytoskeletal rearrangement, migration, invasion, MMP-2/9 expression and cell survival through activation of ERK1/2 and Akt/PKB pathways.…”

Section: Discussionmentioning

confidence: 74%

“…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: 74%

Section: Introductionmentioning

confidence: 99%

Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes

et al. 2007

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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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“…The chemokine receptor, CXCR4, and its endogenous ligand SDF-1 have been shown to be key components in both chemokineinduced leucocyte trafficking (Aiuti et al, 1997(Aiuti et al, , 1999Hamada et al, 1998) and the migration of malignant epithelial cells to the BMS (Koshiba et al, 2000;Muller et al, 2001;Robledo et al, 2001;Murakami et al, 2002;Schrader et al, 2002;Taichman et al, 2002; Sun et al, 2003). This has led to the hypothesis that CXCR4 is the key component of metastatic implantation in bone marrow and that it represents an important therapeutic target for metastatic bone disease.…”

Section: Discussionmentioning

confidence: 99%

“…These include cancers of the prostate (Taichman et al, 2002), kidney (Schrader et al, 2002), lung (Burger et al, 2003) breast (Muller et al, 2001) and skin (Robledo et al, 2001;Murakami et al, 2002). Cells from these tumour types share many of the trafficking characteristics of haematopoietic stem cells (HSC) (Muller et al, 2001).…”

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confidence: 99%

Invasive characteristics of human prostatic epithelial cells: understanding the metastatic process

et al. 2005

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Prostate cancer has a predilection to metastasise to the bone marrow stroma (BMS) by an as yet uncharacterised mechanism. We have defined a series of coculture models of invasion, which simulate the blood/BMS boundary and allow the elucidation of the signalling and mechanics of trans-endothelial migration within the complex bone marrow environment. Confocal microscopy shows that prostate epithelial cells bind specifically to bone marrow endothelial-to-endothelial cell junctions and initiate endothelial cell retraction. Trans-endothelial migration proceeds via an epithelial cell pseudopodial process, with complete epithelial migration occurring after 232743 min. Stromal-derived factor-1 (SDF-1)/CXCR4 signalling induced PC-3 to invade across a basement membrane although the level of invasion was 3.5-fold less than invasion towards BMS (P ¼ 0.0007) or bone marrow endothelial cells (P ¼ 0.004). Maximal SDF-1 signalling of invasion was completely inhibited by 10 mM of the SDF-1 inhibitor T140. However, 10 mM T140 only reduced invasion towards BMS and bone marrow endothelial cells by 59% (P ¼ 0.001) and 29% (P ¼ 0.011), respectively. This study highlights the need to examine the potential roles of signalling molecules and/or inhibitors, not just in single-cell models but in coculture models that mimic the complex environment of the bone marrow.

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Expression of Functional Chemokine Receptors CXCR3 and CXCR4 on Human Melanoma Cells

Cited by 218 publications

References 56 publications

Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes

Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes

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

Invasive characteristics of human prostatic epithelial cells: understanding the metastatic process

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