Women's Cancer Program Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center Los Angeles CA USA.
Department of Pathology and Laboratory Medicine Cedars-Sinai Medical Center Los Angeles CA USA.
J Pathol Clin Res. 2014 Nov 5;1(1):41-53. doi: 10.1002/cjp2.4. eCollection 2015 Jan.
The current standard of care for epithelial ovarian cancer does not discriminate between different histologic subtypes (serous, clear cell, endometrioid and mucinous) despite the knowledge that ovarian carcinoma subtypes do not respond uniformly to conventional platinum/taxane-based chemotherapy. Exploiting addictions and vulnerabilities in cancers with distinguishable molecular features presents an opportunity to develop individualized therapies that may be more effective than the current 'one size fits all' approach. One such opportunity is arginine depletion therapy with pegylated arginine deiminase, which has shown promise in several cancer types that exhibit low levels of argininosuccinate synthetase including hepatocellular and prostate carcinoma and melanoma. Based on the high levels of argininosuccinate synthetase previously observed in ovarian cancers, these tumours have been considered unlikely candidates for arginine depletion therapy. However, argininosuccinate synthetase levels have not been evaluated in the individual histologic subtypes of ovarian carcinoma. The current study is the first to examine the expression of argininosuccinate synthetase at the mRNA and protein levels in large cohorts of primary and recurrent ovarian carcinomas and ovarian cancer cell lines. We show that the normal fallopian tube fimbria and the majority of primary high-grade and low-grade serous ovarian carcinomas express high levels of argininosuccinate synthetase, which tend to further increase in recurrent tumours. In contrast to the serous subtype, non-serous ovarian carcinoma subtypes (clear cell, endometrioid and mucinous) frequently lack detectable argininosuccinate synthetase expression. The in vitro sensitivity of ovarian cancer cell lines to arginine depletion with pegylated arginine deiminase was inversely correlated with argininosuccinate synthetase expression. Our data suggest that the majority of serous ovarian carcinomas are not susceptible to therapeutic intervention with arginine deiminase while a subset of non-serous ovarian carcinoma subtypes are auxotrophic for arginine and should be considered for clinical trials with pegylated arginine deiminase.
目前上皮性卵巢癌的标准治疗方法并未区分不同的组织学亚型（浆液性、透明细胞性、子宫内膜样和黏液性），尽管已经知道卵巢癌亚型对常规铂类/紫杉烷类化疗的反应并不一致。利用具有可区分分子特征的癌症中的成瘾性和脆弱性，为开发可能比当前“一刀切”方法更有效的个体化治疗方法提供了机会。一种这样的机会是使用聚乙二醇化精氨酸脱亚氨酶进行精氨酸耗竭治疗，该方法在几种表现出低水平精氨酸琥珀酸合成酶的癌症类型中显示出了前景，包括肝细胞癌、前列腺癌和黑色素瘤。基于先前在卵巢癌中观察到的高水平精氨酸琥珀酸合成酶，这些肿瘤被认为不太可能成为精氨酸耗竭治疗的候选者。然而，尚未在卵巢癌的各个组织学亚型中评估精氨酸琥珀酸合成酶的水平。本研究首次在大量原发性和复发性卵巢癌以及卵巢癌细胞系中检查了精氨酸琥珀酸合成酶的 mRNA 和蛋白水平表达。我们表明，正常的输卵管纤毛和大多数原发性高级别和低级别浆液性卵巢癌表达高水平的精氨酸琥珀酸合成酶，这些酶在复发性肿瘤中往往进一步增加。与浆液性亚型相反，非浆液性卵巢癌亚型（透明细胞性、子宫内膜样和黏液性）经常缺乏可检测到的精氨酸琥珀酸合成酶表达。卵巢癌细胞系对聚乙二醇化精氨酸脱亚氨酶进行精氨酸耗竭的体外敏感性与精氨酸琥珀酸合成酶的表达呈负相关。我们的数据表明，大多数浆液性卵巢癌对精氨酸脱氨酶的治疗干预不敏感，而一些非浆液性卵巢癌亚型对精氨酸具有辅助依赖性，应考虑进行聚乙二醇化精氨酸脱氨酶的临床试验。
