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高级别浆液性卵巢癌细胞系对生长因子刺激表现出异质性反应。

High-grade serous ovarian cancer cell lines exhibit heterogeneous responses to growth factor stimulation.

作者信息

Bourgeois Danielle L, Kabarowski Karl A, Porubsky Veronica L, Kreeger Pamela K

机构信息

Department of Biomedical Engineering, University of Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705 USA.

出版信息

Cancer Cell Int. 2015 Dec 7;15:112. doi: 10.1186/s12935-015-0263-4. eCollection 2015.

Abstract

BACKGROUND

The factors driving the onset and progression of ovarian cancer are not well understood. Recent reports have identified cell lines that are representative of the genomic pattern of high-grade serous ovarian cancer (HGSOC), in which greater than 90 % of tumors have a mutation in TP53. However, many of these representative cell lines have not been widely used so it is unclear if these cell lines capture the variability that is characteristic of the disease.

METHODS

We investigated six TP53-mutant HGSOC cell lines (Caov3, Caov4, OV90, OVCA432, OVCAR3, and OVCAR4) for migration, MMP2 expression, proliferation, and VEGF secretion, behaviors that play critical roles in tumor progression. In addition to comparing baseline variation between the cell lines, we determined how these behaviors changed in response to four growth factors implicated in ovarian cancer progression: HB-EGF, NRG1β, IGF1, and HGF.

RESULTS

Baseline levels of each behavior varied across the cell lines and this variation was comparable to that seen in tumors. All four growth factors impacted cell proliferation or VEGF secretion, and HB-EGF, NRG1β, and HGF impacted wound closure or MMP2 expression in at least two cell lines. Growth factor-induced responses demonstrated substantial heterogeneity, with cell lines sensitive to all four growth factors, a subset of the growth factors, or none of the growth factors, depending on the response of interest. Principal component analysis demonstrated that the data clustered together based on cell line rather than growth factor identity, suggesting that response is dependent on intrinsic qualities of the tumor cell rather than the growth factor.

CONCLUSIONS

Significant variation was seen among the cell lines, consistent with the heterogeneity of HGSOC.

摘要

背景

卵巢癌发病及进展的驱动因素尚未完全明确。近期报告已鉴定出一些细胞系,它们代表高级别浆液性卵巢癌(HGSOC)的基因组模式,其中超过90%的肿瘤存在TP53突变。然而,许多这些代表性细胞系尚未得到广泛应用,因此尚不清楚这些细胞系是否捕捉到了该疾病特有的变异性。

方法

我们研究了6种TP53突变的HGSOC细胞系(Caov3、Caov4、OV90、OVCA432、OVCAR3和OVCAR4)的迁移、MMP2表达、增殖和VEGF分泌情况,这些行为在肿瘤进展中起关键作用。除了比较细胞系之间的基线差异外,我们还确定了这些行为如何响应与卵巢癌进展相关的四种生长因子:HB-EGF、NRG1β、IGF1和HGF而发生变化。

结果

各细胞系中每种行为的基线水平各不相同,且这种差异与肿瘤中观察到的差异相当。所有四种生长因子均影响细胞增殖或VEGF分泌,并且HB-EGF、NRG1β和HGF在至少两种细胞系中影响伤口愈合或MMP2表达。生长因子诱导的反应表现出显著的异质性,根据所关注的反应,细胞系对所有四种生长因子、部分生长因子或无生长因子敏感。主成分分析表明,数据是根据细胞系而非生长因子类型聚类在一起的,这表明反应取决于肿瘤细胞的内在特性而非生长因子。

结论

细胞系之间存在显著差异,这与HGSOC的异质性一致。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0a6/4672525/27a57bf46bf0/12935_2015_263_Fig1_HTML.jpg

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