Bekos Christine, Muqaku Besnik, Dekan Sabine, Horvat Reinhard, Polterauer Stephan, Gerner Christopher, Aust Stefanie, Pils Dietmar
Department of Obstetrics and Gynecology, Comprehensive Cancer Center (CCC), Medical University of Vienna, 1090 Vienna, Austria.
Department of Analytical Chemistry, University of Vienna, 1090 Vienna, Austria.
Cancers (Basel). 2019 May 20;11(5):698. doi: 10.3390/cancers11050698.
In high grade serous ovarian cancer patients with peritoneal involvement and unfavorable outcome would benefit from targeted therapies. The aim of this study was to find a druggable target against peritoneal metastasis. We constructed a planar-scale free small world-co-association gene expression network and searched for clusters with hub-genes associated to peritoneal spread. Protein expression and impact was validated via immunohistochemistry and correlations of deregulated pathways with comprehensive omics data were used for biological interpretation. A cluster up-regulated in miliary tumors with NECTIN4 as hub-gene was identified and impact on survival validated. High Nectin 4 protein expression was associated with unfavorable survival and (i) reduced expression of HLA genes (mainly MHC I); (ii) with reduced expression of genes from chromosome 22q11/12; (iii) higher BCAM in ascites and in a high-scoring expression cluster; (iv) higher Kallikrein gene and protein expressions; and (v) substantial immunologic differences; locally and systemically; e.g., reduced CD14 positive cells and reduction of different natural killer cell populations. Each three cell lines with high (miliary) or low NECTIN4 expression (non-miliary) were identified. An anti-Nectin 4 antibody with a linked antineoplastic drug-already under clinical investigation-could be a candidate for a targeted therapy in patients with extensive peritoneal involvement.
在伴有腹膜受累且预后不良的高级别浆液性卵巢癌患者中，靶向治疗可能有益。本研究的目的是寻找一个可用于对抗腹膜转移的可成药靶点。我们构建了一个平面尺度的自由小世界共关联基因表达网络，并寻找与腹膜播散相关的枢纽基因簇。通过免疫组织化学验证蛋白质表达及其影响，并利用失调通路与综合组学数据的相关性进行生物学解释。我们鉴定出一个以NECTIN4作为枢纽基因在粟粒状肿瘤中上调的基因簇，并验证了其对生存的影响。NECTIN4蛋白高表达与不良生存相关，且与以下情况有关：（i）HLA基因（主要是MHC I）表达降低；（ii）22q11/12染色体上的基因表达降低；（iii）腹水中以及高评分表达簇中BCAM水平升高；（iv）激肽释放酶基因和蛋白表达升高；以及（v）局部和全身存在显著的免疫差异，例如CD14阳性细胞减少以及不同自然杀伤细胞群体减少。我们鉴定出三株NECTIN4高表达（粟粒状）或低表达（非粟粒状）的细胞系。一种已在临床研究中的、与抗肿瘤药物偶联的抗NECTIN4抗体，可能成为广泛腹膜受累患者靶向治疗的候选药物。
