Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, China.
J Pathol. 2014 Jan;232(1):43-56. doi: 10.1002/path.4258.
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.
我们研究了细胞因子淋巴毒素在人类卵巢癌肿瘤-基质相互作用中的作用。我们发现，淋巴毒素过表达在各种卵巢癌亚型的癌细胞中普遍存在，淋巴毒素-β受体（LTBR）在癌细胞和癌相关成纤维细胞（CAFs）中广泛表达。在单核培养中，我们表明卵巢癌细胞不是淋巴毒素主要反应细胞。另一方面，我们的共培养研究表明，癌细胞衍生的淋巴毒素通过 LTBR-NF-κB 信号诱导基质成纤维细胞中趋化因子的表达。在所产生的趋化因子中，我们发现成纤维细胞分泌的 CXCL11 通过趋化因子受体 CXCR3 促进卵巢癌细胞的增殖和迁移。在卵巢癌活检中，CAFs 中高表达 CXCL11，而原发性卵巢肿瘤中的恶性细胞中存在 CXCR3。此外，CXCR3 的过度表达与卵巢癌的肿瘤分级和淋巴结转移显著相关，进一步支持了 CXCR3 与 CXCL11 相互作用在促进人类卵巢癌生长和转移中的作用。综上所述，这些结果表明，癌细胞衍生的淋巴毒素通过诱导成纤维细胞中的 CXCL11 介导人类卵巢癌中的肿瘤-基质相互作用。我们的发现表明淋巴毒素-LTBR 和 CXCL11-CXCR3 信号代表卵巢癌的治疗靶点。
