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Chemokine Receptor CXCR3 Promotes Colon Cancer Metastasis to Lymph Nodes

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Chemokine Receptor CXCR3 Promotes Colon Cancer Metastasis to Lymph Nodes Oncogene (2007) 26, 4679–4688 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc ORIGINAL ARTICLE Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes K Kawada1,2,5, H Hosogi1,2,5, M Sonoshita1, H Sakashita3, T Manabe3, Y Shimahara2, Y Sakai2, A Takabayashi4, M Oshima1 and MM Taketo1 1Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; 2Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; 3Department of Clinical Pathology, Graduate School of Medicine, Kyoto University, Kyoto, Japan and 4Kitano Hospital Medical Institute, Osaka, Japan Chemokines and their receptors are essential for leuko- inflammatory cytokines, growth factors and/or patho- cyte trafficking, and also implicated in cancer metastasis genic stimuli. Important roles of chemokines and their to specific organs. We have recently demonstrated that receptors have been demonstrated in inflammation, CXCR3 plays a critical role in metastasis of mouse infection, tissue injury, allergy and cardiovascular melanoma cells to lymph nodes. Here, we show that some diseases as well as in malignant tumors. Chemokine human colon cancer cell lines express CXCR3 constitu- receptor CXCR3 is essential for the physiologic and tively. We constructed cells that expressed CXCR3 cDNA pathologic recruitment of plasmacytoid dendritic cell (‘DLD-1-CXCR3’), and compared with nonexpressing precursors, monocytes and natural killer cells to controls by rectal transplantation in nude mice. Although inflamed lymph nodes (LNs) (Cella et al., 1999; both cell lines disseminated to lymph nodes at similar Janatpour et al., 2001; Martin-Fontecha et al., 2004), frequencies at 2 weeks, DLD-1-CXCR3 expanded more and for retention of Th1 lymphocytes within LNs rapidly than the control in 4 weeks. In 6 weeks, 59% of (Yoneyama et al., 2002). On the other hand, chemokine mice inoculated with DLD1-CXCR3 showed macroscopic receptor CCR7 plays a central role in the recruitment of metastasis in para-aortic lymph nodes, whereas only 14% naı¨ ve T cells, some memory T cells, and mature of those with the control (Po0.05). In contrast, dendritic cells to LNs (Cyster, 1999; von Andrian and metastasis to the liver or lung was rare, and unaffected Mempel, 2003). In contrast, the roles of chemokines in by CXCR3 expression. In clinical colon cancer samples, malignant tumors appear complex. Whereas many we found expression of CXCR3 in 34% cases, most of chemokines show antitumor activities by stimulating which had lymph node metastasis. Importantly, patients immune cells or by inhibiting tumor neovascularization with CXCR3-positive cancer showed significantly poorer (angiogenesis), other chemokines may promote tumor prognosis than those without CXCR3, or those expressing growth and metastasis by directly stimulating growth, and CXCR4 or CCR7. These results indicate that activation enhancing cell motility and/or angiogenesis (Balkwill, of CXCR3 with its ligands stimulates colon cancer 2004). Regarding the direct role of chemokines in LN metastasis preferentially to the draining lymph nodes with metastasis, recent reports suggest a critical role for poorer prognosis. chemokine receptors CXCR3 and CCR7 in metastasis Oncogene (2007) 26, 4679–4688; doi:10.1038/sj.onc.1210267; of melanoma and breast cancer (Mu¨ ller et al., 2001; published online 5 February 2007 Robledo et al., 2001; Kawada et al., 2004). In this study, we demonstrate that CXCR3 is Keywords: CXCR3; colon cancer; lymph node; meta- expressed in colon cancer cells, and plays a key role in stasis colon cancer metastasis to LNs, although CCR7 does not. In addition to CXCL9, 10and 11, CCR7 ligand CCL21 can also activate CXCR3 on colon cancer cells. These results also suggest that CXCR3 can be a novel therapeutic target to suppress LN metastasis in colon Introduction cancer. Chemokines are chemotactic polypeptides that cause directed migration of leukocytes, and are induced by Results Correspondence: Professor MM Taketo, Department of Pharmacol- ogy, Graduate School of Medicine, Kyoto University, Yoshida- Expression of chemokine receptors CXCR3, CXCR4 Konoe´ -cho, Sakyo, Kyoto 606-8501, Japan. and CCR7 in colon cancer cell lines E-mail: [email protected] To investigate CXCR3 expression in human colon 5These authors contributed equally to this paper. Received 25 September 2006; revised 14 November 2006; accepted 1 cancer cell lines, we first performed a Western blot December 2006; published online 5 February 2007 analysis. We found expression of CXCR3 at high levels CXCR3 in colon cancer metastasis to lymph nodes K Kawada et al 4680 in five (Colo205, HCT116, HT29, RKO and WiDr) to the draining para-aortic LNs (Kashtan et al., 1992; of 10colon cancer cell lines (Figure 1a). As none of Tsutsumi et al., 2001; Ninomiya et al., 2004). For CCR7 or CXCR4 antibodies commercially available example, it was reported that HT29 metastasized to LNs was suitable for Western-blot analysis, we resorted to in all tumor-bearing mice (10/10) (Tsutsumi et al., 2001), RT–PCR analysis. CCR7 mRNA was expressed only in whereas LS174T did not (0/5) (Kashtan et al., 1992). two (SW480and Caco2) cell lines, whereas CXCR4 Accordingly, we constructed five colon cancer cell lines mRNA was expressed in seven (Colo205, HCT116, that expressed green fluorescent protein (GFP), and HT29, WiDr, SW480, LS174T and Caco2) cell lines determined the metastatic frequencies to LNs by rectal (Figure 1b). We then confirmed expression of CXCR3, injection into nude mice. Six weeks after inoculations, CXCR4 and CCR7 proteins using flow cytometry. we dissected para-aortic LNs, and examined metastatic Consistent with the Western-blot and RT–PCR data, foci using GFP fluorescence. Cell lines Colo205, Colo205, HCT116, HT29, RKO and WiDr expressed HCT116 and RKO produced metastatic foci in LNs at CXCR3 strongly, whereas DLD-1 or SW480did not at modest to high frequencies (8/10, 8/10 and 5/10, levels detectable by these methods (Figure 1c; data not respectively), whereas DLD-1 and SW480metastasized shown for HT29, RKO or WiDr). only at low frequencies (3/22 and 4/20, respectively) The rectal xenograft method offers a convenient (Table 1a). It was also reported that Caco2 metastasized animal model for colorectal cancer that can metastasize to LNs at a low frequency (1/10) with a cecal Figure 1 Expression of chemokine receptors CXCR3, CCR7 and CXCR4 in human colon cancer cell lines. (a) Western-blot analysis of CXCR3 expression. A spleen extract was used as a positive control, whereas b-actin was used as the internal control. (b) An RT– PCR analysis for CCR7 and CXCR4 expression. RNA from spleen was used as a positive control, with b-actin as the internal control. (c) A flow cytometric analysis of Colo205, HCT116, DLD-1 and SW480 cells for CXCR3 (top), CCR7 (middle) and CXCR4 (bottom) expression. Shaded areas represent cells stained with anti-CXCR3, anti-CCR7 mAb or anti-CXCR4 mAb, whereas white areas show cells stained with the isotype-matched control mAb. Oncogene CXCR3 in colon cancer metastasis to lymph nodes K Kawada et al 4681 Table 1 Metastasis frequency of colon cancer cells Cell line CXCR3 CCR7 CXCR4 Number of metastatic LNsa n % (a) Human colon cancer cell lines Colo205 + À + 8/1080 HCT116 + – + 8/1080 RKO + – – 5/1050 DLD-1 – – – 3/22 14 SW480 À + + 4/2020 Cell line Primary tumor Number of metastatic organsc Number Volume (mm3)d LNs (%) Lungs (%) Liver (%) (b) Human colon cancer DLD-1 cells to LNs, lungs and liverb DLD-1-CXCR3 22/22 9057238 13/22 (59)e 2/22 (9) 1/22 (5) DLD-1-EV 22/22 10287334 3/22 (14) 4/22 (18) 1/22 (5) aLN metastases were examined 6 weeks after inoculations of tumor cells (1 Â 106 cells). bMice were killed at 6 weeks after inoculation of tumor cells (1 Â 106 cells). cMetastatic foci were identified macroscopically with GFP fluorescence. dValues are mean7s.d. ePo0.01 compared with DLD-1-EV cells (Fisher’s exact test). transplantation model (Flatmark et al., 2004). Recent in other colon cancer cell lines (HCT116 and HT29) that studies showed that CCR7 was involved in LN meta- expressed CXCR3, but not CCR7 (data not shown). stasis in breast and stomach cancers, and melanoma Consistent with the result, Colo205 cells exhibited the (Mu¨ ller et al., 2001; Wiley et al., 2001; Mashino et al., CXCL10-induced migration, and the neutralizing anti- 2002). Among the colon cancer cell lines tested by CXCR3 antibody significantly suppressed the migratory RT–PCR and flow cytometry, however, we found response in a dose-dependent manner (Figure 2b). This expression of CCR7 only in SW480and Caco2 that anti-CXCR3 antibody did not suppress the CXCL12- rarely metastasized to LNs (Figure 1b and c). These induced migration (Figure 2b), nor did it induce cell results suggest that metastasis of colon cancer to LNs is aggregation or toxicity (data not shown), which suggests associated with rather CXCR3 than CCR7. that the anti-CXCR3 antibody did not inhibit cell motility nonspecifically. As expected, Colo205 cells exhibited the CCL21-induced migration with a little CXCR3-mediated cellular responses of colon cancer cell lower efficiency than CXCL10(Figure 2c). Although line Colo205 in vitro the neutralizing antibodies against CXCR3 and CCL21, In addition to CXCL9, CXCL10and CXCL11, it has respectively, suppressed the migratory response in a been reported that one of the ligands for CCR7, CCL21/ dose-dependent manner, that against CCR7 showed no SLC can also bind to, and activate CXCR3 in mice suppressive effects (Figure 2c). These results indicate (Soto et al., 1998). Also in some human cells, CCL21 is a that CCL21 induces chemotaxis of human colon cancer functional ligand for endogenously expressed CXCR3 cell line Colo205 through CXCR3. Reorganization of (Dijkstra et al., 2004; Poggi et al., 2004). To investigate the actin cytoskeleton is a prerequisite for cell motility whether CXCR3 can transduce the ligand signals in and migration in cultured leukocytes.
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