title: Cancer cell-derived lymphotoxin mediates reciprocal tumour-stromal interactions in human ovarian cancer by inducing CXCL11 in fibroblasts.
abstract: We have investigated the role of cytokine lymphotoxin in tumour-stromal interactions in human ovarian cancer. We found that lymphotoxin overexpression is commonly shared by the cancer cells of various ovarian cancer subtypes, and lymphotoxin-beta receptor (LTBR) is expressed ubiquitously in both the cancer cells and cancer-associated fibroblasts (CAFs). In monoculture, we showed that ovarian cancer cells are not the major lymphotoxin-responsive cells. On the other hand, our co-culture studies demonstrated that the cancer cell-derived lymphotoxin induces chemokine expression in stromal fibroblasts through LTBR-NF-κB signalling. Amongst the chemokines being produced, we found that fibroblast-secreted CXCL11 promotes proliferation and migration of ovarian cancer cells via the chemokine receptor CXCR3. CXCL11 is highly expressed in CAFs in ovarian cancer biopsies, while CXCR3 is found in malignant cells in primary ovarian tumours. Additionally, the overexpression of CXCR3 is significantly associated with the tumour grade and lymph node metastasis of ovarian cancer, further supporting the role of CXCR3, which interacts with CXCL11, in promoting growth and metastasis of human ovarian cancer. Taken together, these results demonstrated that cancer-cell-derived lymphotoxin mediates reciprocal tumour-stromal interactions in human ovarian cancer by inducing CXCL11 in fibroblasts. Our findings suggest that lymphotoxin-LTBR and CXCL11-CXCR3 signalling represent therapeutic targets in ovarian cancer.
authors.affiliation: Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Tat-San
authors.initials: TS
authors.lastname: Lau
authors.forename: Tony Kwok-Hung
authors.initials: TK
authors.lastname: Chung
authors.forename: Tak-Hong
authors.initials: TH
authors.lastname: Cheung
authors.forename: Loucia Kit-Ying
authors.initials: LK
authors.lastname: Chan
authors.forename: Leonard Wing-Hong
authors.initials: LW
authors.lastname: Cheung
authors.forename: So-Fan
authors.initials: SF
authors.lastname: Yim
authors.forename: Nelson Shing-Shun
authors.initials: NS
authors.lastname: Siu
authors.forename: Kwok-Wai
authors.initials: KW
authors.lastname: Lo
authors.forename: May Mei-Yung
authors.initials: MM
authors.lastname: Yu
authors.forename: Hagen
authors.initials: H
authors.lastname: Kulbe
authors.forename: Frances R
authors.initials: FR
authors.lastname: Balkwill
authors.forename: Joseph
authors.initials: J
authors.lastname: Kwong
mesh_terms: D045744:Cell Line, Tumor; D054371:Chemokine CXCL11 / Q000235:genetics / Q000378:metabolism*; D018920:Coculture Techniques; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006723:Hong Kong; D006801:Humans; D053259:Lymphotoxin beta Receptor / Q000235:genetics / Q000378:metabolism*; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D054367:Receptors, CXCR3 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D059016:Tumor Microenvironment
chemical_list: C515202:CXCL11 protein, human; C515187:CXCR3 protein, human; D054371:Chemokine CXCL11; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D054367:Receptors, CXCR3
keywords: CXCL11; CXCR3; Lymphotoxin; cancer-associated fibroblasts; ovarian cancer; tumour microenvironment; tumour-stromal interactions