Role of the CXCR3 chemokine receptor in the tumor progression of ovarian cancer

CXCR3趋化因子受体在肿瘤抑制淋巴细胞中表达并介导其向实体癌的浸润。相应地，CXCR3配体CXCL9和CXCL10的过表达与卵巢癌免疫浸润增强和生存期延长有关。然而，肿瘤细胞本身也可以过表达CXCR3，这与较差的预后相关。因此，除了增强免疫浸润外，肿瘤微环境中CXCL9和CXCL10的诱导也可能刺激肿瘤细胞的不良效应。因此，阐明CXCR3在卵巢癌细胞中的功能作用是必要的。我们的初步结果表明卵巢癌细胞利用CXCR3向恶性腹水迁移。此外，无论原发肿瘤中的表达如何，腹膜转移的肿瘤细胞总是过度表达CXCR3。因此，我们假设CXCR3参与了卵巢癌的腹膜扩散。在第一个子项目中，我们想要研究CXCR3对卵巢癌细胞促瘤特性的影响：增殖、迁移和蛋白酶的诱导。这将在卵巢癌患者腹水源性肿瘤细胞的原代培养中得到验证。在同基因原位卵巢癌小鼠模型中，我们想研究CXCR3敲低和腹腔内抗CXCR3治疗对肿瘤生长和腹膜扩散的影响。我们将在150例晚期高级别浆液性卵巢癌患者的回顾性队列中研究CXCR3在淋巴结、腹膜和网膜转移中的表达，并与临床病理参数进行相关性研究，以进一步支持体外和体内研究结果。在第三个子项目中，我们希望基于筛选算法确定可能参与卵巢癌腹膜转移的其他趋化因子受体。我们相信我们的研究结果将定义CXCR3，可能还有其他趋化因子受体，作为一个新的治疗靶点来解决晚期卵巢癌的主要临床挑战——前列腺转移扩散。

The CXCR3 chemokine receptor is expressed by tumorsuppressive lymphocytes and mediates their infiltration into solid cancers. Correspondingly, overexpression of the CXCR3 ligands CXCL9 and CXCL10 is associated with enhanced immune infiltration and prolonged survival in ovarian cancer. However, the tumor cells themselves can also overexpress CXCR3 which correlates with a worse prognosis. Therefore, besides en-hancing the immune infiltration an induction of CXCL9 and CXCL10 in the tumor microenvironment might also stimulate unwanted effects in the tumor cells. Therefore, elucidating the functional role of CXCR3 in ovarian cancer cells is mandatory. Our preliminary results show that ovarian cancer cells use CXCR3 to migrate towards malignant ascites. Moreover, tumor cells in peritoneal metastases are invariably CXCR3 overex-pressing regardless of the expression in the primary tumors. Therefore we hypothesize that CXCR3 is involved in the peritoneal spread of ovarian cancer.In the first subproject we want to investigate the influence of CXCR3 on tumorpromoting properties of ovarian cancer cells: proliferation, migration and induction of proteases. This will be validated on primary cultures of ascites-derived tumor cells from patients with ovarian cancer. In a syngeneic orthotopic mouse model of ovarian cancer we want to study the effect of CXCR3 knockdown and intraperitoneal anti-CXCR3 therapy on tumor growth and peritoneal spread. Expression of CXCR3 in lymph node, peritoneal, and omental metastases will be studied in a retrospective cohort of 150 patients with advanced high-grade serous ovarian cancer and correlated with clinicopatho-logic parameters to find further support for the results obtained in vitro and in vivo. In the third subproject we want to identify other chemokine receptors that might be involved in peritoneal metastasis of ovarian cancer based on a screening algorithm.We believe that our results will define CXCR3, and possibly other chemokine receptors, as a new therapeutic target to address pretioneal metastatic spread, the major clinical challenge in advanced ovarian cancer.