EGFR is not a major driver for osteosarcoma cell growth in vitro but contributes to starvation and chemotherapy resistance.
EGFR is not a major driver for osteosarcoma cell growth in vitro but contributes to starvation and chemotherapy resistance.
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DOI：
10.1186/s13046-015-0251-5
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发表时间：
2015-11-02
期刊：
影响因子：
--
通讯作者：
Berger W
中科院分区：
文献类型：
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作者：
Sevelda F;Mayr L;Kubista B;Lötsch D;van Schoonhoven S;Windhager R;Pirker C;Micksche M;Berger W
表皮生长因子受体 (EGFR) 信号传导增强是多种人类癌症的标志。然而，近年来积累的数据表明，EGFR 在人类肉瘤中也可能过度激活。本研究的目的是探讨 EGFR 抑制对骨肉瘤细胞系细胞活力的影响及其与化疗反应的相互作用。我们研究了一组人骨肉瘤细胞系的 EGFR 表达和下游信号传导。为了测试其作为治疗靶点的潜在适用性，将吉非替尼对 EGFR 的抑制与骨肉瘤化疗药物相结合，并进行了细胞活力、迁移和细胞死亡测定。骨肉瘤细胞表达明显不同水平的功能性 EGFR，在某些情况下达到很高的水平。骨肉瘤细胞中 EGFR 的功能通过 EGF 介导的 MAPK 和 PI3K/AKT 通路激活（通过 ERK1/2、AKT、S6 和 GSK3β 的磷酸化确定）得到证实。 EGFR 特异性抑制剂吉非替尼阻断 EGF 介导的下游信号激活。在标准体外培养条件下，临床上可达到的吉非替尼剂量仅表现出有限的细胞毒活性，但显着减少了长期集落形成和细胞迁移。相比之下，在血清饥饿条件下，活性吉非替尼剂量明显减少，而 EGF 则促进饥饿存活。重要的是，吉非替尼显着支持阿霉素和甲氨蝶呤在细胞存活和迁移潜力方面的抗骨肉瘤活性。我们的数据表明 EGFR 不是骨肉瘤细胞生长的主要驱动因素，但有助于饥饿和化疗诱导的应激生存。因此，应评估包括 EGFR 抑制剂在内的联合疗法对高级别骨肉瘤患者的治疗效果。本文的在线版本 (doi:10.1186/s13046-015-0251-5) 包含补充材料，可供授权用户使用。
Enhanced signalling via the epidermal growth factor receptor (EGFR) is a hallmark of multiple human carcinomas. However, in recent years data have accumulated that EGFR might also be hyperactivated in human sarcomas. Aim of this study was to investigate the influence of EGFR inhibition on cell viability and its interaction with chemotherapy response in osteosarcoma cell lines. We have investigated a panel of human osteosarcoma cell lines regarding EGFR expression and downstream signalling. To test its potential applicability as therapeutic target, inhibition of EGFR by gefitinib was combined with osteosarcoma chemotherapeutics and cell viability, migration, and cell death assays were performed. Osteosarcoma cells expressed distinctly differing levels of functional EGFR reaching in some cases high amounts. Functionality of EGFR in osteosarcoma cells was proven by EGF-mediated activation of both MAPK and PI3K/AKT pathway (determined by phosphorylation of ERK1/2, AKT, S6, and GSK3β). The EGFR-specific inhibitor gefitinib blocked EGF-mediated downstream signal activation. At standard in vitro culture conditions, clinically achievable gefitinib doses demonstrated only limited cytotoxic activity, however, significantly reduced long-term colony formation and cell migration. In contrast, under serum-starvation conditions active gefitinib doses were distinctly reduced while EGF promoted starvation survival. Importantly, gefitinib significantly supported the anti-osteosarcoma activities of doxorubicin and methotrexate regarding cell survival and migratory potential. Our data suggest that EGFR is not a major driver for osteosarcoma cell growth but contributes to starvation- and chemotherapy-induced stress survival. Consequently, combination approaches including EGFR inhibitors should be evaluated for treatment of high-grade osteosarcoma patients. The online version of this article (doi:10.1186/s13046-015-0251-5) contains supplementary material, which is available to authorized users.