Autocrine VEGF-A/KDR loop protects epithelial ovarian carcinoma cells from anoikis
Autocrine VEGF-A/KDR loop protects epithelial ovarian carcinoma cells from anoikis
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DOI：
10.1002/ijc.23963
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发表时间：
2009-02-01
影响因子：
6.4
通讯作者：
Coomber, Brenda L.
中科院分区：
文献类型：
--
作者：
Sher, Ifat;Adham, Sirin A.;Coomber, Brenda L.
上皮性卵巢癌（EOC）患者通常在晚期诊断，其特征是腹膜间癌转移和大量腹水的产生。血管内皮生长因子-A（VEGF-A）及其主要信号受体VEGFR2（KDR）在原发性卵巢肿瘤、腹水细胞和转移瘤中共表达，提示卵巢上皮癌细胞中存在自分泌VEGF-A/KDR环。在本研究中，我们研究了这种可能性，并探讨了这种自分泌回路在保护EOC细胞凋亡的锚定自由生长条件下（失巢凋亡）的作用。我们发现3种不同的EOC细胞系（Caov3，OVCAR3，SKOV3）表达VEGF-A及其受体，包括KDR。在这些细胞中，KDR是组成性磷酸化的，并在细胞质膜和细胞核中检测到。用KDR激酶活性的特异性内部抑制剂或VEGF-A中和抗体治疗EOC细胞，可消除KDR自磷酸化，并导致细胞在单细胞、无锚定条件下生长时凋亡显著增加。相反，当EOC细胞在粘附单层中生长时，这些封闭剂对细胞活力没有影响。总之，我们的结果表明，自分泌VEGF-A/KDR环存在于EOC细胞中，并且它在保护细胞免受失巢凋亡中起作用。我们的研究结果表明，用VEGF阻断剂治疗EOC患者可能通过降低血管通透性以及诱导腹水中脱落的卵巢癌细胞凋亡来减少腹膜播散。(C)2008 Wiley-Liss，Inc.
Epithelial ovarian carcinoma (EOC) patients are usually diagnosed at an advanced stage, characterized by interperitoneal carcinomatosis and production of large volumes of ascites. Vascular endothelial growth factor-A (VEGF-A) and its main signaling receptor VEGFR2 (KDR) are coexpressed in primary ovarian tumors, ascitic cells and metastases, suggesting the existence of an autocrine VEGF-A/KDR loop in EOC cells. In the present study, we examined this possibility and explored the role of this autocrine loop in protecting EOC cells from apoptosis under anchorage free growth conditions (anoikis). We found that 3 different EOC cell lines (Caov3, OVCAR3, SKOV3) express both VEGF-A and its receptors, including KDR. In these cells, KDR is constitutively phosphorylated and is detected both in the cell plasma membrane and in the nucleus. Treating EOC cells with specific internal inhibitors of KDR kinase activity or a VEGF-A neutralizing antibody abolished KDR autophosphorylation and resulted in significant increase in apoptosis when cells were grown in single-cell, anchorage-free conditions. By contrast, these blocking reagents had no effect on cell viability when EOC cells were grown in adhesive monolayers. In summary, our results indicate that an autocrine VEGF-A/KDR loop exists in EOC cells and that it plays a role in protecting the cells from anoikis. Our results imply that treating EOC patients with VEGF blocking agents may potentially reduce peritoneal dissemination by decreasing vascular permeability as well as inducing apoptosis of shed ovarian cancer cells in ascites. (C) 2008 Wiley-Liss, Inc.