UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers (CVIB), Dept. of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, 924 Westwood Blvd, Suite 615, Los Angeles, CA, 90024, USA.
Dept. of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Sci Rep. 2020 Sep 9;10(1):14819. doi: 10.1038/s41598-020-71799-w.
Previous data suggest that apparent diffusion coefficient (ADC) imaging phenotypes predict survival response to anti-VEGF monotherapy in glioblastoma. However, the mechanism by which imaging may predict clinical response is unknown. We hypothesize that decorin (DCN), a proteoglycan implicated in the modulation of the extracellular microenvironment and sequestration of pro-angiogenic signaling, may connect ADC phenotypes to survival benefit to anti-VEGF therapy. Patients undergoing resection for glioblastoma as well as patients included in The Cancer Genome Atlas (TCGA) and IVY Glioblastoma Atlas Project (IVY GAP) databases had pre-operative imaging analyzed to calculate pre-operative ADC values, the average ADC in the lower distribution using a double Gaussian mixed model. ADC values were correlated to available RNA expression from these databases as well as from RNA sequencing from patient derived mouse orthotopic xenograft samples. Targeted biopsies were selected based on ADC values and prospectively collected during resection. Surgical specimens were used to evaluate for DCN RNA and protein expression by ADC value. The IVY Glioblastoma Atlas Project Database was used to evaluate DCN localization and relationship with VEGF pathway via in situ hybridization maps and RNA sequencing data. In a cohort of 35 patients with pre-operative ADC imaging and surgical specimens, DCN RNA expression levels were significantly larger in high ADC tumors (41.6 vs. 1.5; P = 0.0081). In a cohort of 17 patients with prospectively targeted biopsies there was a positive linear correlation between ADC levels and DCN protein expression between tumors (Pearson R = 0.3977; P = 0.0066) and when evaluating different targets within the same tumor (Pearson R = 0.3068; P = 0.0139). In situ hybridization data localized DCN expression to areas of microvascular proliferation and immunohistochemical studies localized DCN protein expression to the tunica adventitia of blood vessels within the tumor. DCN expression positively correlated with VEGFR1 & 2 expression and localized to similar areas of tumor. Increased ADC on diffusion MR imaging is associated with high DCN expression as well as increased survival with anti-VEGF therapy in glioblastoma. DCN may play an important role linking the imaging features on diffusion MR and anti-VEGF treatment efficacy. DCN may serve as a target for further investigation and modulation of anti-angiogenic therapy in GBM.
先前的数据表明，表观扩散系数（ADC）成像表型可预测胶质母细胞瘤患者接受抗 VEGF 单药治疗的生存反应。然而，影像学预测临床反应的机制尚不清楚。我们假设，核心蛋白聚糖（DCN），一种被认为可调节细胞外微环境和隔离促血管生成信号的蛋白聚糖，可能将 ADC 表型与抗 VEGF 治疗的生存获益联系起来。接受胶质母细胞瘤切除术的患者以及 The Cancer Genome Atlas（TCGA）和 IVY Glioblastoma Atlas Project（IVY GAP）数据库中的患者，术前进行影像学分析以计算术前 ADC 值，使用双高斯混合模型计算下分布的平均 ADC 值。将 ADC 值与这些数据库中的可用 RNA 表达以及来自患者来源的原位异种移植样本的 RNA 测序进行相关分析。根据 ADC 值选择靶向活检，并在切除过程中进行前瞻性采集。手术标本用于通过 ADC 值评估 DCN RNA 和蛋白质表达。使用 IVY Glioblastoma Atlas Project 数据库通过原位杂交图谱和 RNA 测序数据评估 DCN 定位及其与 VEGF 途径的关系。在 35 名具有术前 ADC 成像和手术标本的患者队列中，高 ADC 肿瘤的 DCN RNA 表达水平显著更高（41.6 与 1.5；P=0.0081）。在 17 名具有前瞻性靶向活检的患者队列中，肿瘤之间的 ADC 水平与 DCN 蛋白表达呈正线性相关（Pearson R=0.3977；P=0.0066），以及评估同一肿瘤内的不同靶标时（Pearson R=0.3068；P=0.0139）。原位杂交数据将 DCN 表达定位到微血管增殖区域，免疫组织化学研究将 DCN 蛋白表达定位到肿瘤内血管的外膜。DCN 表达与 VEGFR1 和 2 表达呈正相关，且定位于肿瘤的相似区域。扩散磁共振成像上的 ADC 增加与 DCN 高表达以及抗 VEGF 治疗在胶质母细胞瘤中的生存获益相关。DCN 可能在将扩散磁共振成像上的成像特征与抗 VEGF 治疗疗效联系起来方面发挥重要作用。DCN 可能作为进一步研究和调节 GBM 抗血管生成治疗的靶点。
