Division of Ocular Oncology and Pathology, Department of Ophthalmology and Visual Sciences, and Department of Radiation Oncology, Vanderbilt Eye Institute and Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, United States.
Department of Pharmacology and Toxicology, Department of Ophthalmology, Department of Biochemistry and Molecular Biology, and Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, United States.
Invest Ophthalmol Vis Sci. 2024 Jun 3;65(6):18. doi: 10.1167/iovs.65.6.18.
Regression of retinoblastoma vitreous seeds (VS) during intravitreal chemotherapy can be delayed, resulting in supernumerary injections. Similarly, VS relapse may not be clinically evident at first. A predictive biomarker of tumor regression and relapse could help guide real-time clinical decision making. Retinoblastoma is an oxygen-sensitive tumor; paradoxically, VS survive in the hypoxic vitreous. We hypothesized that VS elaborate pro-angiogenic cytokines. The purpose was to determine if pro-angiogenic cytokine signatures from aqueous humor could serve as a biomarker of VS response to treatment.
Multiplex ELISA was performed on aqueous from rabbit eyes with human retinoblastoma VS xenografts to identify expressed proangiogenic cytokines and changes in aqueous cytokine levels during intravitreal treatment were determined. Confirmatory RNAscope in situ hybridization for VEGF-A was performed on human retinoblastoma tumor sections and VS xenografts from rabbits. For human eyes undergoing intravitreal chemotherapy, serial aqueous VEGF-A levels measured via VEGF-A-specific ELISA were compared to clinical response.
VEGF-A was highly expressed in human retinoblastoma VS in the xenograft model, and was the only proangiogenic cytokine that correlated with VS disease burden. In rabbits, aqueous VEGF-A levels decreased in response to therapy, consistent with quantitative VS reduction. In patients, aqueous VEGF-A levels associated with clinical changes in disease burden (regression, stability, or relapse), with changes in VEGF-A levels correlating with clinical response.
Aqueous VEGF-A levels correlate with extent of retinoblastoma VS, suggesting that aqueous VEGF-A may serve as a predictive molecular biomarker of treatment response.
眼内化疗期间视网膜母细胞瘤玻璃体内种子（VS）的消退可能会延迟，导致需要额外注射。同样，VS 的复发最初可能在临床上并不明显。肿瘤消退和复发的预测性生物标志物可以帮助指导实时临床决策。视网膜母细胞瘤是一种对氧气敏感的肿瘤；矛盾的是，VS 在缺氧的玻璃体中存活。我们假设 VS 分泌促血管生成细胞因子。本研究旨在确定房水中的促血管生成细胞因子特征是否可作为 VS 对治疗反应的生物标志物。
对患有人视网膜母细胞瘤 VS 异种移植物的兔眼房水进行多重 ELISA 检测，以确定表达的促血管生成细胞因子，并确定玻璃体内治疗期间房水中细胞因子水平的变化。对人视网膜母细胞瘤肿瘤切片和兔的 VS 异种移植物进行了 VEGF-A 的 RNAscope 原位杂交验证。对于接受眼内化疗的人眼，通过 VEGF-A 特异性 ELISA 测量的连续房水 VEGF-A 水平与临床反应进行了比较。
VEGF-A 在异种移植模型中的人视网膜母细胞瘤 VS 中高度表达，是唯一与 VS 疾病负担相关的促血管生成细胞因子。在兔子中，房水 VEGF-A 水平随着治疗而降低，与定量 VS 减少一致。在患者中，房水 VEGF-A 水平与疾病负担的临床变化相关（消退、稳定或复发），VEGF-A 水平的变化与临床反应相关。
房水 VEGF-A 水平与视网膜母细胞瘤 VS 的程度相关，表明房水 VEGF-A 可能作为治疗反应的预测性分子生物标志物。
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