Hubrecht Institute-KNAW and University Medical Center, Utrecht, The Netherlands.
Dis Model Mech. 2013 Sep;6(5):1159-66. doi: 10.1242/dmm.012377. Epub 2013 May 29.
Angiogenesis, the emergence of vessels from an existing vascular network, is pathologically associated with tumor progression and is of great interest for therapeutic intervention. PTEN is a frequently mutated tumor suppressor and has been linked to the progression of many types of tumors, including hemangiosarcomas in zebrafish. Here, we report that mutant zebrafish embryos lacking functional Pten exhibit enhanced angiogenesis, accompanied by elevated levels of phosphorylated Akt (pAkt). Inhibition of phosphoinositide 3-kinase (PI3K) by LY294002 treatment and application of sunitinib, a widely used anti-angiogenic compound, suppressed enhanced angiogenesis in Pten mutants. Vegfaa has a crucial role in angiogenesis and vegfaa expression was upregulated in embryos lacking functional Pten. Interestingly, vegfaa expression was also upregulated in hemangiosarcomas from haploinsufficient adult zebrafish Pten mutants. Elevated vegfaa expression in mutant embryos lacking functional Pten was suppressed by LY294002. Surprisingly, sunitinib treatment dramatically enhanced vegfaa expression in Pten mutant embryos, which might account for tumor relapse in human patients who are treated with sunitinib. Combined treatment with suboptimal concentrations of sunitinib and LY294002 rescued enhanced angiogenesis in pten mutant embryos without the dramatic increase in vegfaa expression, suggesting a new approach for therapeutic intervention in VEGFR-signaling-dependent tumors.
血管生成，即从现有血管网络中出现新的血管，与肿瘤的进展密切相关，是治疗干预的重要目标。PTEN 是一种经常发生突变的肿瘤抑制因子，与多种类型的肿瘤进展有关，包括斑马鱼的血管肉瘤。在这里，我们报告说，缺乏功能性 Pten 的突变斑马鱼胚胎表现出增强的血管生成，伴随着磷酸化 Akt（pAkt）水平的升高。LY294002 抑制磷脂酰肌醇 3-激酶（PI3K）的作用以及广泛应用的抗血管生成化合物舒尼替尼的应用抑制了 Pten 突变体中增强的血管生成。Vegfaa 在血管生成中起着关键作用，缺乏功能性 Pten 的胚胎中 vegfaa 的表达上调。有趣的是，hemangiosarcomas 中 vegfaa 的表达也在功能不全的 Pten 突变体成年斑马鱼中上调。LY294002 抑制了缺乏功能性 Pten 的突变胚胎中 vegfaa 的表达。令人惊讶的是，舒尼替尼治疗显著增强了 Pten 突变胚胎中 vegfaa 的表达，这可能是接受舒尼替尼治疗的人类患者肿瘤复发的原因。用舒尼替尼和 LY294002 的亚最佳浓度联合治疗挽救了 pten 突变胚胎中增强的血管生成，而 vegfaa 表达没有显著增加，这表明了一种针对 VEGFR 信号依赖性肿瘤的新治疗干预方法。
