CXCL10 Promotes Osteolytic Bone Metastasis by Enhancing Cancer Outgrowth and Osteoclastogenesis

Lee, Jong-Ho; Kim, Ha‐Neui; Kim, Kyung-Ok; Jin, Won Jong; Lee, Seungbok; Kim, Hong Hee; Ha, Hyunil; Lee, Zang Hee

doi:10.1158/0008-5472.can-12-0481

Cited by 99 publications

(86 citation statements)

References 35 publications

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“…30, 31, 32, 33, 34, 35, 36, 37, 38 The localization of CXCR3 in tumor cells, endothelial cells and tumor-infiltrating lymphocytes in our HGSC samples matches earlier results in clear cell ovarian cancer. 39 By using splice variant-specific antibodies, Furuya et al 39 demonstrated that endothelial cells mainly expressed CXCR3-B, whereas cancer cells mainly expressed CXCR3-A.…”

Section: Discussionsupporting

confidence: 89%

CXCR3 mediates ascites-directed tumor cell migration and predicts poor outcome in ovarian cancer patients

et al. 2017

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Intraabdominal tumor dissemination is a major hallmark of epithelial ovarian cancer (EOC), but the underlying mechanisms have not been fully elucidated. The CXCR3 chemokine receptor supports migration of tumor cells to metastatic sites, but its role in ovarian cancer metastasis is largely unknown. Herein, we first screened two independent cohorts of high-grade serous ovarian cancers (HGSCs, discovery set n=60, validation set n=117) and 102 metastatic lesions for CXCR3 expression. In primary tumors, CXCR3 was particularly overexpressed by tumor cells at the invasive front. In intraabdominal metastases, tumor cells revealed a strong CXCR3 expression regardless of its expression in the corresponding primary tumor, suggesting a selection of CXCR3-overexpressing cancer cells into peritoneal niches. In support of this, CXCR3 mediated the migration of tumor cell lines OVCAR3 and SKOV3 toward malignant ascites, which was inhibited by a monoclonal anti-CXCR3 antibody in vitro. These results were prospectively validated in ascites-derived tumor cells from EOC patients ex vivo (n=9). Moreover, tumor cell-associated overexpression of CXCR3 in advanced ovarian cancer patients was associated with a reduced progression-free survival (PFS) and overall survival (OS), which remained independent of optimal debulking, age, FIGO stage and lymph node involvement (PFS: hazard ratio (HR) 2.11, 95% confidence interval (CI) 1.30–3.45, P=0.003; OS: HR 2.36, 95% CI 1.50–3.71, P<0.001). These results in ovarian cancer patients identify CXCR3 as a potential new target to confine peritoneal spread in ovarian cancer after primary cytoreductive surgery.

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Section: Discussionsupporting

confidence: 89%

CXCR3 mediates ascites-directed tumor cell migration and predicts poor outcome in ovarian cancer patients

et al. 2017

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“…We found that transcripts of CCL5, CCL9 and CXCL10 increased 12-, 6.8-, and 4.5-fold, respectively, in Colon26L5-CUG2 cells compared to those in Colon26L5-Vec cells (data not shown). Many lines of evidence have supported that CCL5, CCL9 and CXCL10 are involved in metastasis of various cancer cells (27)(28)(29), and have shown that IFN signaling induces upregulation of these chemokines (30)(31)(32). We therefore assume that upregulated chemokines through the STAT1-IFN axis enhance migration of colon cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Cancer upregulated gene 2, a novel oncogene, enhances migration and drug resistance of colon cancer cells via STAT1 activation

Malilas¹,

Koh²,

Kim³

et al. 2013

International Journal of Oncology

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Abstract. Cancer upregulated gene (CUG) 2, as a novel oncogene, has been predominantly detected in various cancer tissues, such as ovary, liver, lung and colon. We recently showed that CUG2 elevates STAT1 activity, leading to resistance to infection by oncolytic vesicular stomatitis virus. To investigate a possible role for CUG2-induced activation of STAT1 in oncogenesis, we first established a colon cancer cell line stably expressing CUG2 (Colon26L5-CUG2). Colon26L5-CUG2 exhibited higher levels not only in phosphorylation of STAT1, but also phosphorylation of Jak1/Tyk2 compared to that of the control (Colon26L5-Vec) cell line. Inhibition of Akt or ERK activity reduced phosphorylation of STAT1 in Colon26L5-CUG2 cells whereas inhibition of p38 MAPK did not significantly decrease levels of STAT1 phosphorylation, indicating that cell proliferation signals may be involved in CUG2-mediated activation of STAT1. Suppression of STAT1 expression diminished cell migration and wound healing compared to the control cells. In addition, since CUG2 expression conferred resistance to DNA damage caused by doxorubicin treatment, we investigated whether STAT1 is involved in resistance to doxorubicininduced cell death. We found that STAT1 was not activated in Colon26L5-Vec cells while phosphorylated STAT1 was maintained in Colon26L5-CUG2 cells during doxorubicin treatment. Furthermore, suppression of STAT1 expression sensitized Colon26L5-CUG2 cells to doxorubicin-induced apoptosis whereas the control cells exhibited resistance to doxorubicin. Taken together, our results suggest that CUG2 enhances metastasis and drug resistance through STAT1 activation, which eventually contributes to tumor progression. IntroductionTo discover new genes that play a crucial role in common tumorigenesis regardless of tissue origin, we analyzed commonly upregulated unknown genes in 242 normal and 300 tumor samples originating from 11 different tissues using the Affymetrix gene chip system. An Affymetrix fragment, later named cancer upregulated gene (CUG) 2 was identified as a candidate gene that is commonly upregulated in various tumor tissues such as ovary, liver, lung and colon. This CUG2 was mapped to chromosome 6q22.32; it spans ~8.5 kb with a three-exon structure and encodes a 88-amino acid polypeptide (1). Further study has revealed that CUG2 is a new component of centromere required for a proper kinetochore function during cell division (2). Of interest, CUG2 has been shown to harbor an oncogenic effect in a transplanted model using NIH3T3 cells expressing CUG2, in a manner similar to Ras (1). Although CUG2 overexpression leads to activated Ras and MAPKs including p38 MAPK, which eventually facilitates oncolytic reoviral replication (3), CUG2 contrastingly provides resistance to oncolytic vesicular stomatitis virus infection through activation of STAT1 as shown in our recent study (4).Although STAT1 is well known as a master transcription factor for IFN-related intracellular signaling, leading to antiviral activity, several lines of evidence hav...

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“…Similarly, C-X-C motif chemokine 10 (CXCL10) has been reported to facilitate the trafficking of C-X-C chemokine receptor type 3 (CXCR3)-expressing cancer cells to bone, which augments its own production, enhances tumor growth and at the same time promotes osteoclastic differentiation, indicating that the CXCL10/CXCR3 axis may be another attractive therapeutic target for osteolytic metastasis [61]. …”

Section: Homing To the Bonementioning

confidence: 99%

New therapeutic targets for cancer bone metastasis

Krzeszinski

Wan

2015

Trends in Pharmacological Sciences

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Bone metastases are dejected consequences of many types of tumors including breast, prostate, lung, kidney and thyroid cancers. This complicated process begins with the successful tumor cell epithelial–mesenchymal transition, escape from the original site, and penetration into circulation. The homing of tumor cells to the bone depends on both tumor-intrinsic traits and various molecules supplied by the bone metastatic niche. The colonization and growth of cancer cells in the osseous environment, which awaken their dormancy to form micro- and macro-metastasis, involve an intricate interaction between the circulating tumor cells and local bone cells including osteoclasts, osteoblasts, adipocytes and macrophages. In this review, we discuss the most recent advances in the identification of new molecules and novel mechanisms during each step of bone metastasis that may serve as promising therapeutic targets.

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CXCL10 Promotes Osteolytic Bone Metastasis by Enhancing Cancer Outgrowth and Osteoclastogenesis

Cited by 99 publications

References 35 publications

CXCR3 mediates ascites-directed tumor cell migration and predicts poor outcome in ovarian cancer patients

CXCR3 mediates ascites-directed tumor cell migration and predicts poor outcome in ovarian cancer patients

Cancer upregulated gene 2, a novel oncogene, enhances migration and drug resistance of colon cancer cells via STAT1 activation

New therapeutic targets for cancer bone metastasis

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