肿瘤浸润区中癌症干细胞标志物 ALDH1A3 的高表达与人类胶质母细胞瘤的总生存期更短相关。
The predominant expression of cancer stem cell marker ALDH1A3 in tumor infiltrative area is associated with shorter overall survival of human glioblastoma.
机构信息
Department of Neurosurgery and Spine Surgery, University hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany.
Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
出版信息
BMC Cancer. 2020 Jul 17;20(1):672. doi: 10.1186/s12885-020-07153-0.
BACKGROUND
ALDH1A3 is a cancer stem cell marker in neoplasms including glioblastoma (GBM). However, the comprehensive role of ALDH1A3 in GBM remains unclear. This study attempted to investigate the expression of ALDH1A3 in human GBM tissues and its association with clinical parameters.
METHODS
Thirty primary GBM and 9 control were enrolled in this study. ALDH1A3 mRNA and protein expression levels were detected by RT-PCR and western blot, respectively. Immunohistochemistry and immunofluorescence staining were performed to evaluate the regional and cellular expression manner of ALDH1A3. The association of ALDH1A3 expression with multiple clinical parameters was analyzed.
RESULTS
ALDH1A3 protein level, but not mRNA level, in a subgroup of GBM was significantly higher than that in the control group. ALDH1A3 immunoreactivity was detected heterogeneously in individual GBMs. Fifteen of 30 cases showed a positive of ALDH1A3 immunoreactivity which was predominantly observed in the tumor infiltrative area (TI). Double immunofluorescence staining revealed a co-localization of ALDH1A3 with GFAP in glial-shaped cells and in tumor cells. ALDH1A3 immunoreactivity was often merged with CD44, but not with CD68. Moreover, ALDH1A3 expression was positively associated with the tumor edema grade and inversely with overall survival (OS) (median OS: 16 months vs 10 months), but with neither MGMT promoter methylation status nor Ki67 index in GBM. An upregulation of ALDH1A3 was accompanied by a reduced expression of STAT3β and p-STAT3β.
CONCLUSIONS
Inter- and intra-tumoral heterogeneous expression of ALDH1A3 was exhibited in GBMs. A high immunoreactivity of ALDH1A3 in tumor infiltrative area was associated with shorter OS, especially in patients with MGMT promoter methylation. Our findings propose ALDH1A3 not only as a predictive biomarker but also as a potential target for personalized therapy of GBM.
背景
ALDH1A3 是包括神经胶质瘤（GBM）在内的肿瘤中的癌症干细胞标志物。然而，ALDH1A3 在 GBM 中的全面作用仍不清楚。本研究试图探讨 ALDH1A3 在人 GBM 组织中的表达及其与临床参数的关系。
方法
本研究纳入了 30 例原发性 GBM 和 9 例对照。通过 RT-PCR 和 Western blot 分别检测 ALDH1A3 mRNA 和蛋白表达水平。通过免疫组化和免疫荧光染色评估 ALDH1A3 的区域和细胞表达方式。分析 ALDH1A3 表达与多种临床参数的关系。
结果
亚组 GBM 中 ALDH1A3 蛋白水平而非 mRNA 水平明显高于对照组。个别 GBM 中 ALDH1A3 免疫反应呈异质性。30 例中有 15 例显示 ALDH1A3 免疫反应阳性，主要见于肿瘤浸润区（TI）。双重免疫荧光染色显示 ALDH1A3 与 GFAP 在胶质样细胞和肿瘤细胞中存在共定位。ALDH1A3 免疫反应常与 CD44 融合，但与 CD68 不融合。此外，ALDH1A3 表达与肿瘤水肿程度呈正相关，与总生存期（OS）呈负相关（中位 OS：16 个月比 10 个月），但与 GBM 中 MGMT 启动子甲基化状态或 Ki67 指数无关。ALDH1A3 的上调伴随着 STAT3β 和 p-STAT3β 的表达下调。
结论
GBM 中存在 ALDH1A3 的肿瘤内和肿瘤间异质性表达。肿瘤浸润区高免疫反应性 ALDH1A3 与较短的 OS 相关，尤其是在 MGMT 启动子甲基化的患者中。我们的研究结果表明，ALDH1A3 不仅可以作为预测生物标志物，也可以作为 GBM 个体化治疗的潜在靶点。
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