The Role of GDF15 in Regulating the Canonical Pathways of the Tumor Microenvironment in Wild-Type p53 Ovarian Tumor and Its Response to Chemotherapy.
The Role of GDF15 in Regulating the Canonical Pathways of the Tumor Microenvironment in Wild-Type p53 Ovarian Tumor and Its Response to Chemotherapy.
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DOI：
10.3390/cancers12103043
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发表时间：
2020-10-19
期刊：
影响因子：
5.2
通讯作者：
Wong KK
中科院分区：
文献类型：
--
作者：
Izaguirre DI;Ng CW;Kwan SY;Kun EH;Tsang YTM;Gershenson DM;Wong KK
由于对化疗的抵抗，野生型p53卵巢癌患者的生存率似乎比突变型p53患者更差。这一现象背后的机制尚不清楚。本研究的目的是确定潜在的生物标志物调节p53，赋予使用在体外和体内研究的阻力。在卵巢癌细胞系和原位小鼠模型中，生长分化因子15（GDF 15）的表达被证明是由p53控制的。GDF 15敲低的A2780细胞系诱导的肿瘤的组织学和RNAseq研究揭示了间质/肿瘤的比率和经典途径被分泌型GDF 15修饰。背景资料：卵巢癌的标准治疗是手术，然后是由铂剂如顺铂和紫杉烷样紫杉醇组成的化疗组合。我们以前观察到，卵巢癌p53野生型患者的生存率低于p53突变患者。因此，更好地了解野生型p53的上皮性卵巢癌细胞对顺铂治疗的分子变化，可以揭示新的化学耐药机制。方法：应用基因表达谱分析法检测顺铂对卵巢癌细胞株A2780野生型p53的影响。编码分泌性蛋白质生长分化因子15（GDF 15）的基因被鉴定为在体外被顺铂处理高度诱导。这在一组野生型和突变型p53卵巢癌细胞系以及小鼠原位模型中得到了进一步验证。通过组织学和RNA测序进一步分析小鼠肿瘤组织。结果：GDF 15是顺铂或卡铂在具有野生型p53的卵巢癌细胞系中高度诱导的基因之一。在体外和体内进一步证实了野生型p53诱导的GDF 15表达和GDF 15赋予的化疗抗性。本研究还发现，GDF 15-kinkdown（GDF 15-KD）肿瘤具有较少的基质成分，并且在顺铂治疗后，基质细胞和癌细胞成分中具有与对照肿瘤不同的激活和抑制的经典途径。结论：来自野生型p53癌细胞的GDF 15表达可以调节肿瘤微环境中响应于顺铂的典型途径，这是化学抗性的可能机制。
Patients with wild-type p53 ovarian cancer appear to have a poorer survival rate than those with mutant p53 due to resistance to chemotherapy. The mechanism underlying this observation is not clearly understood. The aim of this study was to identify potential biomarkers regulated by p53 that conferred resistance using in vitro and in vivo studies. Growth differentiation factor 15 (GDF15) expression was demonstrated to be controlled by p53 in both ovarian cancer cell lines and orthotopic mouse models. The histological and RNAseq studies of the GDF15-knocked down, A2780 cell line-induced tumor revealed that the ratio and canonical pathways of stromal/tumor were modified by secretory GDF15. Background: The standard treatment of ovarian cancer is surgery followed by a chemotherapeutic combination consisting of a platinum agent, such as cisplatin and a taxane-like paclitaxel. We previously observed that patients with ovarian cancer wild-type for p53 had a poorer survival rate than did those with p53 mutations. Thus, a better understanding of the molecular changes of epithelial ovarian cancer cells with wild-type p53 in response to treatment with cisplatin could reveal novel mechanisms of chemoresistance. Methods: Gene expression profiling was performed on an ovarian cancer cell line A2780 with wild-type p53 treated with cisplatin. A gene encoding a secretory protein growth differentiation factor 15 (GDF15) was identified to be highly induced by cisplatin treatment in vitro. This was further validated in a panel of wild-type and mutant p53 ovarian cancer cell lines, as well as in mouse orthotopic models. The mouse tumor tissues were further analyzed by histology and RNA-seq. Results: GDF15 was identified as one of the highly induced genes by cisplatin or carboplatin in ovarian cancer cell lines with wild-type p53. The wild-type p53-induced expression of GDF15 and GDF15-confered chemotherapy resistance was further demonstrated in vitro and in vivo. This study also discovered that GDF15-knockdown (GDF15-KD) tumors had less stromal component and had different repertoires of activated and inhibited canonical pathways in the stromal cell and cancer cell components from that of the control tumors after cisplatin treatment. Conclusions: GDF15 expression from the wild-type p53 cancer cells can modulate the canonical pathways in the tumor microenvironment in response to cisplatin, which is a possible mechanism of chemoresistance.
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作者：
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