Autocrine regulation of glioblastoma cell cycle progression, viability and radioresistance through the VEGF-VEGFR2 (KDR) interplay
Autocrine regulation of glioblastoma cell cycle progression, viability and radioresistance through the VEGF-VEGFR2 (KDR) interplay
复制标题
DOI：
10.4161/cc.7.16.6442
复制
发表时间：
2008-08-15
期刊：
影响因子：
4.3
通讯作者：
Bartek, Jiri
中科院分区：
文献类型：
--
作者：
Knizetova, Petra;Ehrmann, Jiri;Bartek, Jiri
血管内皮生长因子（VEGF）在恶性脑肿瘤的血管生成和进展中起着至关重要的作用。考虑到肿瘤微环境的重要性，以及旁分泌VEGF信号在胶质母细胞瘤（GBM）生物学中的作用，我们探讨了VEGF对人类星形细胞瘤行为的潜在自分泌控制。使用一系列的细胞和分子生物学方法来研究一组星形细胞瘤（III级和IV级/GBM）衍生的细胞系和一系列低级别和高级别星形细胞瘤的临床标本，我们发现VEGF和VEGF受体（VEGF受体）的共表达通常发生在星形细胞瘤细胞中。我们发现VEGF分泌和VEGF诱导的生物学效应（调节细胞周期进程和增强胶质母细胞瘤细胞的活力）以自分泌方式发挥作用。此外，我们证明自分泌VEGF信号转导是通过VEGFR 2（KDR）介导的，并且涉及c-Raf/ MAPK、PI 3 K/Akt和PLC/PKC通路的共激活。选择性抑制剂（SU 1498）阻断VEGFR 2可在无干扰培养条件下消除VEGF介导的星形细胞瘤细胞生长和活力增强。此外，这种干扰VEGF-VEGFR 2信号增强电离辐射诱导的肿瘤细胞死亡。在临床标本中，VEGF和VEGF在星形胶质细胞肿瘤细胞中共表达，且较高的VEGF表达与肿瘤进展相关，从而支持体内功能性VEGF-VEGFR信号传导的相关性。总的来说，我们的研究结果与VEGF-VEGFR 2（KDR）相互作用作为恶性星形细胞瘤生长和放射抗性的一个因素的潜在自分泌作用一致，从而支持这种信号级联作为治疗靶点的候选资格，可能与放射治疗相结合。
Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis and progression of malignant brain tumors. Given the significance of tumor microenvironment in general, and the established role of paracrine VEGF signaling in glioblastoma (GBM) biology in particular, we explored the potential autocrine control of human astrocytoma behavior by VEGF. Using a range of cell and molecular biology approaches to study a panel of astrocytoma (grade III and IV/GBM)-derived cell lines and a series of clinical specimens from low- and high-grade astrocytomas, we show that co-expression of VEGF and VEGF receptors (VEGFRs) occurs commonly in astrocytoma cells. We found VEGF secretion and VEGF-induced biological effects (modulation of cell cycle progression and enhanced viability of glioblastoma cells) to function in an autocrine manner. Morevover, we demonstrated that the autocrine VEGF signaling is mediated via VEGFR2 (KDR), and involves co-activation of the c-Raf/ MAPK, PI3K/Akt and PLC/PKC pathways. Blockade of VEGFR2 by the selective inhibitor (SU1498) abrogated the VEGF-mediated enhancement of astrocytoma cell growth and viability under unperturbed culture conditions. In addition, such interference with VEGF-VEGFR2 signaling potentiated the ionizing radiation-induced tumor cell death. In clinical specimens, both VEGFRs and VEGF were co-expressed in astroglial tumor cells, and higher VEGF expression correlated with tumor progression, thereby supporting the relevance of functional VEGF-VEGFR signaling in vivo. Overall, our results are consistent with a potential autocrine role of the VEGF-VEGFR2 (KDR) interplay as a factor contributing to malignant astrocytoma growth and radioresistance, thereby supporting the candidacy of this signaling cascade as a therapeutic target, possibly in combination with radiotherapy.