Department of Urology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
Neoplasia. 2012 Apr;14(4):259-70. doi: 10.1593/neo.12442.
Epithelial ovarian cancer is the fourth leading cause of death from gynecologic malignancies in the United States. Most cases are diagnosed at late stages, with the solid tumor masses growing as peritoneal implants, or floating within the ascitic fluid (peritoneal ovarian carcinomatosis). Despite aggressive surgical "debulking," recurrence of recalcitrant disease is frequent with poor patient survival. Efforts to improve survival rates are hindered by lack of biomarkers that can detect and effectively treat ovarian cancer in its early stages. Urokinase plasminogen activator receptor (uPAR) is a multifunctional receptor involved in a myriad of tumor cell processes. However, the role of host uPAR in ovarian cancer is still elusive. To define the potential proinflammatory role of uPAR in ovarian cancer, first, using a syngeneic murine model in uPAR(-/-) mice, we found that ablation of uPAR restrained tumor take and peritoneal implants and prolonged the survival of uPAR(-/-) mice compared with their uPAR(+/+) counterparts. Ascitic fluid accumulation was significantly decreased in uPAR(-/-) mice with decreased macrophage infiltration. Second, in vitro mechanistic studies revealed that host uPAR is involved in the multiple steps of peritoneal metastatic cascade. Third, we evaluated the prognostic utility of tumor and stromal uPAR in human ovarian cancer tissue microarray. In summary, our studies indicated that uPAR plays a significant role in ovarian cancer cell-stromal crosstalk and contributes to increased vascular permeability and inflammatory ovarian cancer microenvironment. This provides a rationale for targeting the uPAR with either specific neutralizing antibodies or targeting its downstream inflammatory effectors in patients with ovarian cancer.
上皮性卵巢癌是美国第四大导致妇科恶性肿瘤死亡的原因。大多数病例在晚期诊断，实体肿瘤块在腹膜种植部位生长，或在腹水（腹膜卵巢癌转移）中漂浮。尽管进行了积极的手术“减瘤”，但难治性疾病的复发仍然频繁，患者生存状况较差。由于缺乏能够在早期检测和有效治疗卵巢癌的生物标志物，因此改善生存率的努力受到了阻碍。尿激酶型纤溶酶原激活物受体（uPAR）是一种多功能受体，参与多种肿瘤细胞过程。然而，宿主 uPAR 在卵巢癌中的作用仍然难以捉摸。为了确定 uPAR 在卵巢癌中潜在的促炎作用，首先，我们使用 uPAR(-/-) 小鼠的同基因小鼠模型发现，与 uPAR(+/+) 小鼠相比，uPAR 缺失可抑制肿瘤的发生和腹膜种植，并延长 uPAR(-/-) 小鼠的生存时间。uPAR(-/-) 小鼠的腹水积聚明显减少，巨噬细胞浸润减少。其次，体外机制研究表明宿主 uPAR 参与了腹膜转移级联的多个步骤。第三，我们评估了肿瘤和基质 uPAR 在人卵巢癌组织微阵列中的预后效用。总之，我们的研究表明 uPAR 在卵巢癌细胞-基质相互作用中发挥重要作用，并导致血管通透性增加和炎症性卵巢癌微环境。这为在卵巢癌患者中使用特异性中和抗体或靶向其下游炎症效应器来靶向 uPAR 提供了依据。
