CXCL9 and CXCL10 predict survival and are regulated by cyclooxygenase inhibition in advanced serous ovarian cancer

Bronger, Holger; Singer, J. David; Windmüller, Claudia; Reuning, Ute; Zech, Daniela; Delbridge, Claire; Dorn, Julia; Kiechle, Marion; Schmalfeldt, Barbara; Schmitt, Manfred; Avril, Stefanie

doi:10.1038/bjc.2016.172

Cited by 212 publications

(201 citation statements)

References 48 publications

(70 reference statements)

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“…CXCL9 and CXCL10 are chemokines that bind to CXCR3 leading to the recruitment of tumor‐suppressive T cells and NK cells into tumor stroma . Higher concentrations of these chemokines in tumors is associated with a higher lymphocyte infiltration and better overall survival in ovarian and other cancers . In contrast, other studies have suggested a protumorigenic role of these two chemokines in cancer progression and metastasis .…”

Section: Discussionmentioning

confidence: 99%

Activation of a protumorigenic IFNγ/STAT1/IRF‐1 signaling pathway in keratinocytes following exposure to solar ultraviolet light

Blazanin

Cheng

Carbajal

et al. 2019

Molecular Carcinogenesis

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In this study, we evaluated the role of signal transducer and activator of transcription 1 (STAT1) in response to acute solar ultraviolet (SUV) radiation in mouse epidermis. Analysis of the epidermis from SUV‐irradiated mice revealed rapid phosphorylation of STAT1 (pSTAT1) on both tyrosine (tyr701) and serine (ser727) residues and increased levels of IRF‐1 while later timepoints showed increased levels of unphosphorylated STAT1 (uSTAT1). STAT1 activation led to upregulation of several proinflammatory chemokine mRNAs in epidermis including Cxcl9, Cxcl10, and Ccl2, as well as, the immune checkpoint inhibitor Pd‐l1. In addition, mRNA and protein levels of cyclooxygenase‐2 (Cox‐2/COX2) were upregulated in epidermis following exposure to SUV. Mice with keratinocyte‐specific STAT1 deletion did not exhibit increased IRF‐1 or proinflammatory gene expression in epidermis. Furthermore, epidermal COX‐2 induction after SUV exposure was significantly reduced in mice with keratinocyte‐specific deletion of STAT1. Additionally, SUV irradiation rapidly upregulated interferon gamma (IFNγ) mRNA in the epidermis and that skin resident epidermal CD3 + T‐cells were the source of IFNγ production. IFNγ receptor‐deficient mice confirmed dependency of STAT1 activation, proinflammatory gene expression and COX‐2 upregulation in the epidermis on paracrine IFNγ signaling. Furthermore, keratinocyte‐specific STAT1‐deficiency reduced proliferation and hyperplasia due to SUV irradiation and this was associated with decreased immune infiltration of mast cells in the dermis. Collectively, the current results demonstrate that exposure to SUV leads to upregulation of IFNγ and downstream pSTAT1/IRF‐1/uSTAT1 signaling in the epidermis. Further study of this pathway could lead to identification of novel targets for the prevention of nonmelanoma skin cancer.

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Section: Discussionmentioning

confidence: 99%

Activation of a protumorigenic IFNγ/STAT1/IRF‐1 signaling pathway in keratinocytes following exposure to solar ultraviolet light

Blazanin

Cheng

Carbajal

et al. 2019

Molecular Carcinogenesis

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“…14 Detailed patient characteristics are given in Table 1. All patients underwent standard debulking surgery followed by platinum-based chemotherapy.…”

Section: Methodsmentioning

confidence: 99%

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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“…Indeed, it has been widely reported that a higher density of TILs, such as T and B lymphocytes, is associated with increased overall survival and chemo-radiosensitivity in OC [121][122][123][124]. Previous reports have confirmed that higher levels of the cytokines IL-6 and VEGF are associated with chemoresistance, are both markers for poor prognosis in OC and exhibit pro-tumorigenic effects, such as promoting angiogenesis [125,126]. These studies highlight key insights that are applicable to both basic OC research and to the prevention and treatment of OC.…”

Section: Immunosuppressive Mechanisms and Chronic Inflammationmentioning

confidence: 97%

Mechanism for the Decision of Ovarian Surface Epithelial Stem Cells to Undergo Neo-Oogenesis or Ovarian Tumorigenesis

Zheng

Hong

et al. 2018

Cell Physiol Biochem

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The ovary is surrounded by a whitish layer of mesodermally derived ovarian surface epithelium (OSE) that lines the intraembryonic celom and comprises simple squamous to cuboidal to low pseudostratified columnar epithelial cells. Its integrity is maintained by simple desmosomes, incomplete tight junctions, several integrins and cadherins. Recent research has found that ovarian stem cells (OSCs) exist within the OSE and may be responsible for both neo-oogenesis and ovarian cancer during adult life. The factors determining whether OSCs undergo neo-oogenesis or ovarian cancer are of great interest to researchers and clinicians. Accumulating evidence suggests the mechanism for the decision of ovarian surface epithelial stem cells to undergo either neo-oogenesis or ovarian cancer transformation may comprise both internal and external factors. Here, we review recent progress on how the internal factors, including genes, signaling pathways and lncRNA: OSE stem cells mediate the development and progression of ovarian cancer through various genes such as p53, KRAS, BRAF, and PTEN, and mutations in PIK3CA, and through various signaling pathways, including TGF-B pathway, Wnt signaling pathway, Notch signaling pathway, NF-kB signal transducer and transcriptional activator 3 (STAT3) pathway and Hedghog (HH) pathway. A series of expressions of IncRNA have changed in epithelial ovarian cancer tissues and cell lines compared to normal ovarian tissues and cell lines. As well as external factors, including incessant ovulation, gonadotropin and chronicinflammation: Frequent ovulation, without long-term dormancy, increases the risk of illness, because repeated rupture and repair at the ovulation site provides an opportunity for the accumulation of genetic aberrations; FSH affects all aspects of ovarian cancer metastasis, such as inhibition of apoptosis, through Induction of increased expression of VEGFA (VEGF) to support tumor growth, promote vascular growth, and possibly alter certain oncogenic pathways, thereby promoting proliferation and invasive phenotypic inflammation contributes to tumorigenesis, which help determine whether OSCs undergo neo-oogenesis or ovarian tumorigenesis. Understanding this issue is critical for developing novel strategies for premature ovarian failure and ovarian cancer prevention and therapy.

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CXCL9 and CXCL10 predict survival and are regulated by cyclooxygenase inhibition in advanced serous ovarian cancer

Cited by 212 publications

References 48 publications

Activation of a protumorigenic IFNγ/STAT1/IRF‐1 signaling pathway in keratinocytes following exposure to solar ultraviolet light

Activation of a protumorigenic IFNγ/STAT1/IRF‐1 signaling pathway in keratinocytes following exposure to solar ultraviolet light

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

Mechanism for the Decision of Ovarian Surface Epithelial Stem Cells to Undergo Neo-Oogenesis or Ovarian Tumorigenesis

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