The expression level of VEGFR2 regulates mechanotransduction, tumor growth and metastasis of high grade serous ovarian cancer cells

IF 4.5 3区 生物学 Q2 CELL BIOLOGY
Elisabetta Grillo , Cosetta Ravelli , Michela Corsini , Mattia Domenichini , Maria Scamozzi , Daniela Zizioli , Davide Capoferri , Roberto Bresciani , Chiara Romani , Stefania Mitola
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Abstract

Recent data shows that alterations in the expression and/or activation of the vascular endothelial growth factor receptor 2 (VEGFR2) in high grade serous ovarian cancer (HGSOC) modulate tumor progression. However, controversial results have been obtained, showing that in some cases VEGFR2 inhibition can promote tumorigenesis and metastasis. Thus, it is urgent to better define the role of the VEGF/VEGFR2 system to understand/predict the effects of its inhibitors administered as anti-angiogenic in HGSOC. Here, we modulated the expression levels of VEGFR2 and analyzed the effects in two cellular models of HGSOC. VEGFR2 silencing (or its pharmacological inhibition) promote the growth and invasive potential of OVCAR3 cells in vitro and in vivo. Consistent with this, the low levels of VEGFR2 in OV7 cells are associated with more pronounced proliferative and motile phenotypes when compared to OVCAR3 cells, and VEGFR2 overexpression in OV7 cells inhibits cell growth. In vitro data confirmed that VEGFR2 silencing in OVCAR3 cells favors the acquisition of an invasive phenotype by loosening cell-ECM contacts, reducing the size and the signaling of focal adhesion contacts (FAs). This is translated into a reduced FAK activity at FAs, ECM-dependent alterations of mechanical forces through FAs and YAP nuclear translocation. Together, the data show that low expression, silencing or inhibition of VEGFR2 in HGSOC cells alter mechanotransduction and lead to the acquisition of a pro-proliferative/invasive phenotype which explains the need for a more cautious use of anti-VEGFR2 drugs in ovarian cancer.
VEGFR2 的表达水平调控着高级别浆液性卵巢癌细胞的机械传导、肿瘤生长和转移。
最近的数据显示,高级别浆液性卵巢癌(HGSOC)中血管内皮生长因子受体 2(VEGFR2)的表达和/或激活的改变可调节肿瘤的进展。然而,有争议的结果表明,在某些情况下,抑制血管内皮生长因子受体 2 可促进肿瘤发生和转移。因此,当务之急是更好地界定 VEGF/VEGFR2 系统的作用,以了解/预测其抑制剂作为抗血管生成药物在 HGSOC 中的作用。在这里,我们调节了 VEGFR2 的表达水平,并分析了两种 HGSOC 细胞模型的效果。VEGFR2 沉默(或其药物抑制)促进了 OVCAR3 细胞在体外和体内的生长和侵袭潜力。与此相一致的是,与 OVCAR3 细胞相比,OV7 细胞中低水平的 VEGFR2 与更明显的增殖和运动表型相关,而 OV7 细胞中 VEGFR2 的过表达会抑制细胞生长。体外数据证实,OVCAR3 细胞中的 VEGFR2 沉默通过松动细胞-ECM 接触、减小病灶粘附接触(FA)的大小和信号传导,有利于获得侵袭表型。这将转化为 FAs 上 FAK 活性的降低、通过 FAs 机械力的 ECM 依赖性改变以及 YAP 核转位。这些数据共同表明,HGSOC 细胞中 VEGFR2 的低表达、沉默或抑制改变了机械传导,并导致获得一种促增殖/侵袭性表型,这解释了在卵巢癌中更谨慎使用抗 VEGFR2 药物的必要性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
European journal of cell biology
European journal of cell biology 生物-细胞生物学
CiteScore
7.30
自引率
1.50%
发文量
80
审稿时长
38 days
期刊介绍: The European Journal of Cell Biology, a journal of experimental cell investigation, publishes reviews, original articles and short communications on the structure, function and macromolecular organization of cells and cell components. Contributions focusing on cellular dynamics, motility and differentiation, particularly if related to cellular biochemistry, molecular biology, immunology, neurobiology, and developmental biology are encouraged. Manuscripts describing significant technical advances are also welcome. In addition, papers dealing with biomedical issues of general interest to cell biologists will be published. Contributions addressing cell biological problems in prokaryotes and plants are also welcome.
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