Abstract
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.
Highlights
Intraabdominal metastasis remains a fundamental clinical challenge in advanced ovarian cancer and accounts for disease recurrence and death in most of the patients.[1]
CXCR3 is functionally active in EOC cells and mediates tumor cell migration toward malignant ascites receptor was localized in tumor cells, endothelial cells and tumor- We explored the function of CXCR3 in ovarian cancer using infiltrating lymphocytes, whereas stromal fibroblasts were nega- the two well-established epithelial ovarian cancer (EOC) cell lines tive (Figure 1a)
This study in ovarian cancer patients identifies CXCR3 expressed by tumor cells as a novel independent prognostic marker of reduced progression-free survival (PFS) and overall survival (OS)
Summary
Intraabdominal metastasis remains a fundamental clinical challenge in advanced ovarian cancer and accounts for disease recurrence and death in most of the patients.[1]. The CXCR3 chemokine receptor is such a conceivable metastasis-promoting factor as it is upregulated in ovarian carcinomas[9,10] and involved in cancer growth and metastasis of other solid cancers.[11,12] Physiologically, it is predominantly expressed on T lymphocytes and natural killer cells.[13] Recently, we have shown that high intratumoral concentrations of the two CXCR3 ligands CXCL9 and CXCL10 are associated with improved survival in high-grade serous ovarian cancer (HGSC).[14] This protective effect of intratumoral CXCR3 chemokines is generally attributed to an enhanced infiltration of CXCR3positive tumor-suppressive lymphocytes.[15,16] tumorpromoting regulatory T cells use CXCR3 to home into ovarian cancers.[14,17] We speculated that other mechanisms may be involved in the protective effect of high intratumoral CXCL9 and CXCL10 concentrations, namely the prevention of CXCR3-mediated tumor cell migration out of the primary tumor. These results imply that CXCR3 may contribute to tumor cell dissemination within the abdominal cavity in humans, making it a potential target structure to control peritoneal spread after primary debulking surgery
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