Izadpanah Amin, Daneshimehr Fatemeh, Willingham Kurtis, Barabadi Zahra, Braun Stephen E, Dumont Aaron, Mostany Ricardo, Chandrasekar Bysani, Alt Eckhard U, Izadpanah Reza
Applied Stem Cell Laboratory, Medicine/Heart and Vascular Institute, Tulane University School of Medicine, New Orleans, LA, United States.
Division of Regenerative Medicine, Tulane National Primate Research Center, Covington, LA, United States.
Front Oncol. 2022 Aug 15;12:893820. doi: 10.3389/fonc.2022.893820. eCollection 2022.
Increased vascularization, also known as neoangiogenesis, plays a major role in many cancers, including glioblastoma multiforme (GBM), by contributing to their aggressive growth and metastasis. Although anti-angiogenic therapies provide some clinical improvement, they fail to significantly improve the overall survival of GBM patients. Since various pro-angiogenic mediators drive GBM, we hypothesized that identifying targetable genes that broadly inhibit multiple pro-angiogenic mediators will significantly promote favorable outcomes. Here, we identified TRAF3IP2 (TRAF3-interacting protein 2) as a critical regulator of angiogenesis in GBM. We demonstrated that knockdown of TRAF3IP2 in an intracranial model of GBM significantly reduces vascularization. Targeting TRAF3IP2 significantly downregulated VEGF, IL6, ANGPT2, IL8, FZGF2, PGF, IL1β, EGF, PDGFRB, and VEGFR2 expression in residual tumors. Our data also indicate that exogenous addition of VEGF partially restores angiogenesis by TRAF3IP2-silenced cells, suggesting that TRAF3IP2 promotes angiogenesis through VEGF- and non-VEGF-dependent mechanisms. These results indicate the anti-angiogenic and anti-tumorigenic potential of targeting TRAF3IP2 in GBM, a deadly cancer with limited treatment options.
血管生成增加，也称为新生血管形成，在包括多形性胶质母细胞瘤（GBM）在内的许多癌症中起着重要作用，它促进了癌症的侵袭性生长和转移。尽管抗血管生成疗法带来了一些临床改善，但它们未能显著提高GBM患者的总体生存率。由于多种促血管生成介质驱动GBM，我们假设鉴定出能广泛抑制多种促血管生成介质的可靶向基因将显著促进良好的治疗结果。在此，我们鉴定出TRAF3IP2（TRAF3相互作用蛋白2）是GBM血管生成的关键调节因子。我们证明，在GBM的颅内模型中敲低TRAF3IP2可显著减少血管生成。靶向TRAF3IP2可显著下调残留肿瘤中VEGF、IL6、ANGPT2、IL8、FZGF2、PGF、IL1β、EGF、PDGFRB和VEGFR2的表达。我们的数据还表明，外源性添加VEGF可部分恢复TRAF3IP2沉默细胞的血管生成，这表明TRAF3IP2通过VEGF依赖性和非VEGF依赖性机制促进血管生成。这些结果表明，在治疗选择有限的致命癌症GBM中，靶向TRAF3IP2具有抗血管生成和抗肿瘤发生的潜力。
