Département de Microbiologie et Infectiologie, Faculté de Médecine, Université de Sherbrooke, 3001, 12ième Avenue Nord, Sherbrooke, J1H 5N4, Canada.
J Ovarian Res. 2010 Jan 18;3:1. doi: 10.1186/1757-2215-3-1.
The production of ascites is a common complication of ovarian cancer. Ascites constitute a unique tumor microenvironment that may affect disease progression. In this context, we recently showed that ovarian cancer ascites may protect tumor cells from TRAIL-induced apoptosis. In this study, we sought to determine whether the prosurvival effect of ascites affects disease-free intervals.
Peritoneal fluids were obtained from 54 women undergoing intra-abdominal surgery for suspected ovarian cancer (44 cancers and 10 benign diseases). The ability of peritoneal fluids to protect from TRAIL was assessed in the ovarian cancer cell line CaOV3, and IC(50 )were determined. The anti-apoptotic activity of 6 ascites against cisplatin, paclitaxel, doxorubicin, etoposide and vinorelbine was also assessed in CaOV3 cells, and the prosurvival activity of two ascites was assessed in 9 primary ovarian cancer cultures.
Among the 54 peritoneal fluids tested, inhibition of TRAIL cytotoxicity was variable. Fluids originating from ovarian cancer were generally more protective than fluids from non-malignant diseases. Most of the 44 ovarian cancer ascites increased TRAIL IC(50 )and this inhibitory effect did not correlate strongly with the protein concentration in these ascites or the levels of serum CA125, a tumor antigen which is used in the clinic as a marker of tumor burden. The effect of ascites on cisplatin- and paclitaxel-induced cell death was assessed with 4 ascites having inhibitory effect on TRAIL-induced cell death and 2 that do not. The four ascites with prosurvival activity against TRAIL had some inhibitory on cisplatin and/or paclitaxel. Two ovarian cancer ascites, OVC346 and OVC509, also inhibited TRAIL cytotoxicity in 9 primary cultures of ovarian tumor and induced Akt activation in three of these primary cultures. Among a cohort of 35 patients with ascites, a threshold of TRAIL IC(50 )with ascites/IC(50 )without ascites > 2 was associated with shorter disease-free interval.
The prosurvival activity of ascites against TRAIL is associated with shorter disease-free interval, which may be explained, at least in part, by ascites-induced cisplatin/paclitaxel resistance. Our findings suggest that ascites may contain prosurvival factors that protect against TRAIL and chemotherapy and consequently affect disease progression.
腹水的产生是卵巢癌的常见并发症。腹水构成了一个独特的肿瘤微环境，可能影响疾病的进展。在这种情况下，我们最近表明，卵巢癌腹水可能保护肿瘤细胞免受 TRAIL 诱导的细胞凋亡。在这项研究中，我们试图确定腹水的生存促进作用是否会影响无病间隔。
从 54 名因疑似卵巢癌而接受腹腔内手术的妇女（44 例癌症和 10 例良性疾病）中获得腹膜液。在卵巢癌细胞系 CaOV3 中评估腹膜液对 TRAIL 的保护能力，并确定 IC50。还评估了 6 种腹水对顺铂、紫杉醇、多柔比星、依托泊苷和长春瑞滨在 CaOV3 细胞中的抗凋亡活性，并评估了两种腹水在 9 种原发性卵巢癌细胞培养物中的生存促进活性。
在测试的 54 种腹膜液中，TRAIL 细胞毒性的抑制作用各不相同。来源于卵巢癌的液体通常比来源于非恶性疾病的液体更具保护性。大多数来自 44 例卵巢癌腹水的腹水增加了 TRAIL IC50，这种抑制作用与这些腹水中的蛋白浓度或血清 CA125 水平相关性不强，CA125 是一种在临床上作为肿瘤负荷标志物的肿瘤抗原。用 4 种对 TRAIL 诱导的细胞死亡具有抑制作用的腹水和 2 种不具有抑制作用的腹水评估腹水对顺铂和紫杉醇诱导的细胞死亡的影响。对 TRAIL 具有生存促进作用的四种腹水对顺铂和/或紫杉醇有一定的抑制作用。两种卵巢癌细胞腹水 OVC346 和 OVC509，也抑制了 9 种原发性卵巢肿瘤培养物中的 TRAIL 细胞毒性，并在其中 3 种原发性培养物中诱导 Akt 激活。在 35 例腹水患者队列中，腹水 TRAIL IC50/无腹水 TRAIL IC50>2 的阈值与无病间隔较短相关。
腹水对 TRAIL 的生存促进作用与无病间隔较短有关，这至少部分可以解释为腹水诱导的顺铂/紫杉醇耐药。我们的发现表明，腹水可能含有保护细胞免受 TRAIL 和化疗的生存促进因子，从而影响疾病的进展。
