The chemokine receptor CXCR3 is expressed on malignant B cells and mediates chemotaxis

Trentin, Livio; Agostini, Carlo; Facco, Monica; Piazza, Francesco; Perin, Alessandra; Siviero, Marta; Gurrieri, Carmela; Galvan, Silvia; Adami, Fausto; Zambello, Renato; Semenzato, Gianpietro

doi:10.1172/jci7335

Cited by 138 publications

(117 citation statements)

References 30 publications

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“…[38][39][40][41] In contrast to the lack of CXCR3 on normal B cells, the malignant counterparts of B cells have been reported to express CXCR3, particularly B cells from patients with CLL. 42,43 Similarly to these findings, MM cells express CXCR3 (Figure 2). However, only three of them (U-1958, Karpas 707 and L363) migrated in response to IP-10.…”

Section: Figuresupporting

confidence: 70%

Expression and function of chemokine receptors in human multiple myeloma

et al. 2003

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Section: Figuresupporting

confidence: 70%

Expression and function of chemokine receptors in human multiple myeloma

et al. 2003

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“…33 Although the expression of CXCR3 mRNA is not regulated by MUM1 as shown in our MUM1-inducible system, it is constitutively expressed on malignant B cells obtained from patients with B-CLL, whose cells show chemotaxis towards MIG. 34 Interestingly, two B-CLL cell lines expressing MUM1 also expressed MIG and CXCR3 proteins in our study. Our data suggest that MUM1 expression may be one of the mechanisms that induce MIG expression and that the MIG-CXCR3 system may constitute an autocrine loop that promotes cellular proliferation in a fraction of the B-CLL cells that express MUM1.…”

Section: Discussionsupporting

confidence: 51%

Multiple myeloma oncogene 1 (MUM1)/interferon regulatory factor 4 (IRF4) upregulates monokine induced by interferon-γ (MIG) gene expression in B-cell malignancy

et al. 2005

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MUM1 (multiple myeloma oncogene 1)/IRF4 (interferon regulatory factor 4) is a transcription factor that is activated as a result of t(6;14)(p25;q32) in multiple myeloma. MUM1 expression is seen in various B-cell lymphomas and predicts an unfavorable outcome in some lymphoma subtypes. To elucidate its role in B-cell malignancies, we prepared MUM1-expressing Ba/F3 cells, which proliferated until higher cellular density than the parental cells, and performed cDNA microarray analysis to identify genes whose expression is regulated by MUM1. We found that the expression of four genes including FK506-binding protein 3 (FKBP3), the monokine induced by interferonc(MIG), Fas apoptotic inhibitory molecule (Faim) and Zinc-finger protein 94 was altered in the MUM1-expressing cells. We then focused on MIG since its expression was immediately upregulated by MUM1. In reporter assays, MUM1 activated the MIG promoter in cooperation with PU.1, and the interaction between MUM1 and the MIG promoter sequence was confirmed. The expression of MIG was correlated with that of MUM1 in B-CLL cell lines, and treatment with neutralizing antibodies against MIG and its receptor, CXCR3, slightly inhibited the proliferation of two MUM1-expressing lines. These results suggest that MUM1 plays roles in the progression of B-cell lymphoma/ leukemia by regulating the expression of various genes including MIG.

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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: 73%

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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The chemokine receptor CXCR3 is expressed on malignant B cells and mediates chemotaxis

Cited by 138 publications

References 30 publications

Expression and function of chemokine receptors in human multiple myeloma

Expression and function of chemokine receptors in human multiple myeloma

Multiple myeloma oncogene 1 (MUM1)/interferon regulatory factor 4 (IRF4) upregulates monokine induced by interferon-γ (MIG) gene expression in B-cell malignancy

Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes

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