Centre de Recherche en Reproduction Animale, Faculté de Médecine Vétérinaire, Université de Montréal, St-Hyacinthe, Québec, Canada.
Transl Oncol. 2013 Jun 1;6(3):226-33. doi: 10.1593/tlo.13136. Print 2013 Jun.
Although angiogenesis has been proposed as a therapeutic target for the treatment of ovarian granulosa cell tumor (GCT), its potential has not been evaluated in controlled studies. To do so, we used the Pten (tm1Hwu/tm1Hwu); Ctnnb1 (tm1Mmt/+);Amhr2 (tm3(cre)Bhr/+) (PCA) mouse model, which develops GCTs that mimic the advanced disease in women. A monoclonal anti-vascular endothelial growth factor A (VEGFA) antibody was administered weekly to PCA mice beginning at 3 weeks of age. By 6 weeks of age, anti-VEGFA therapy significantly decreased tumor weights relative to controls (P < .05) and increased survival, with all treated animals but none of the controls surviving to 8 weeks of age. Analyses of PCA tumors showed that anti-VEGFA treatment resulted in significant decreases in tumor cell proliferation and microvessel density relative to controls (P < .05). However, treatment did not have a significant effect on apoptosis or tumor necrosis. The VEGFA receptor 2 (VEGFR2) signaling effector p44/p42 mitogen-activated protein kinase (MAPK), whose activity is associated with cell proliferation, was significantly less phosphorylated (i.e., activated) in tumors from the treated group (P < .05). Conversely, no significant difference was found in the activation of protein kinase B, a VEGFR2 signaling effector associated with cell survival. Together, these results suggest that anti-VEGFA therapy is effective at inhibiting GCT growth in the PCA model and acts by reducing microvascular density and cell proliferation through inhibition of the VEGFR2-MAPK pathway. Findings from this preclinical model therefore support the investigation of targeting VEGFA for the adjuvant treatment of GCT in women.
虽然血管生成已被提议作为治疗卵巢颗粒细胞瘤 (GCT) 的治疗靶点，但在对照研究中尚未评估其潜力。为此，我们使用了 Pten (tm1Hwu/tm1Hwu); Ctnnb1 (tm1Mmt/+);Amhr2 (tm3(cre)Bhr/+) (PCA) 小鼠模型，该模型可发展出类似于女性晚期疾病的 GCT。从 3 周龄开始，每周给 PCA 小鼠注射一种抗血管内皮生长因子 A (VEGFA) 的单克隆抗体。到 6 周龄时，与对照组相比，抗 VEGFA 治疗显著降低了肿瘤重量（P <.05）并提高了存活率，所有接受治疗的动物均存活至 8 周龄，而对照组无一存活。对 PCA 肿瘤的分析表明，与对照组相比，抗 VEGFA 治疗导致肿瘤细胞增殖和微血管密度显著降低（P <.05）。然而，治疗对细胞凋亡或肿瘤坏死没有显著影响。VEGFA 受体 2 (VEGFR2) 信号效应物 p44/p42 丝裂原活化蛋白激酶 (MAPK) 的活性与细胞增殖相关，在治疗组的肿瘤中，其磷酸化（即激活）显著降低（P <.05）。相反，在与细胞存活相关的 VEGFR2 信号效应物蛋白激酶 B 的激活中未发现显著差异。综上所述，这些结果表明，抗 VEGFA 治疗在 PCA 模型中有效抑制 GCT 生长，其作用机制是通过抑制 VEGFR2-MAPK 通路减少微血管密度和细胞增殖。因此，该临床前模型的研究结果支持针对 VEGFA 作为女性 GCT 辅助治疗的研究。
