MACC1 对人恶性脑胶质瘤进展及患者不良预后的影响。
Impact of MACC1 on human malignant glioma progression and patients' unfavorable prognosis.
机构信息
Corresponding Author: Ulrike Stein, PhD, Experimental and Clinical Research Center, Charité University Medicine Berlin and the Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany.
出版信息
Neuro Oncol. 2013 Dec;15(12):1696-709. doi: 10.1093/neuonc/not136. Epub 2013 Nov 11.
BACKGROUND
Metastasis-associated in colon cancer 1 (MACC1) has been established as an independent prognostic indicator of metastasis formation and metastasis-free survival for patients with colon cancer and other solid tumors. However, no data are available concerning MACC1 expression in human astrocytic tumors. Glioblastoma multiforme (GBM) is the most prevalent primary brain tumor of adulthood, and due to its invasive and rapid growth, patients have unfavorable prognoses. Although these tumors rarely metastasize, their invasive and migratory behavior is similar to those of metastatic cells of tumors of different origin. Thus, we hypothesized that MACC1 may be involved in progression of human gliomas.
METHODS
We performed real-time measurements of proliferation and migration in MACC1-transfected GBM cell lines (U138, U251) and evaluated tumor formation in organotypic hippocampal slice cultures of mice. Semiquantitative and quantitative real-time reverse transcription PCR analyses were performed for MACC1 and for its transcriptional target c-Met in human astrocytoma of World Health Organization grade II (low-grade astrocytoma) and GBM biopsies. Data were validated by MACC1 immunohistochemistry in independent matched samples of low-grade astrocytoma and GBM.
RESULTS
MACC1 increases the proliferative, migratory, and tumor-formation abilities of GBM cells. The c-Met inhibitor crizotinib reduced MACC1-induced migration and tumor formation in organotypic hippocampal slice cultures of mice. Analyzing patients' biopsies, MACC1 expression increased concomitantly with increasing World Health Organization grade. Moreover, MACC1 expression levels allowed discrimination of dormant and recurrent low-grade astrocytomas and of primary and secondary GBM. Strong MACC1 expression correlated with reduced patient survival.
CONCLUSIONS
MACC1 may represent a promising biomarker for prognostication and a new target for treatment of human gliomas.
背景
结肠癌转移相关基因 1（MACC1）已被确立为结肠癌和其他实体肿瘤患者转移形成和无转移生存的独立预后指标。然而，目前尚无关于人类星形细胞瘤中 MACC1 表达的相关数据。多形性胶质母细胞瘤（GBM）是成人中最常见的原发性脑肿瘤，由于其侵袭性和快速生长，患者预后不良。尽管这些肿瘤很少转移，但它们的侵袭和迁移行为与不同来源肿瘤的转移性细胞相似。因此，我们假设 MACC1 可能参与人类神经胶质瘤的进展。
方法
我们在 MACC1 转染的 GBM 细胞系（U138、U251）中进行了实时增殖和迁移测量，并在小鼠器官型海马切片培养物中评估了肿瘤形成。对人类星形细胞瘤组织活检进行了 MACC1 及其转录靶标 c-Met 的半定量和实时定量反转录 PCR 分析，分为世界卫生组织（WHO）分级 II 级（低级别星形细胞瘤）和 GBM。通过在独立的低级别星形细胞瘤和 GBM 匹配样本中进行 MACC1 免疫组织化学验证数据。
结果
MACC1 增加了 GBM 细胞的增殖、迁移和肿瘤形成能力。c-Met 抑制剂克唑替尼可降低 MACC1 诱导的小鼠器官型海马切片培养物中的迁移和肿瘤形成。分析患者活检，MACC1 表达随着 WHO 分级的增加而增加。此外，MACC1 表达水平可区分休眠和复发性低级别星形细胞瘤以及原发性和继发性 GBM。MACC1 表达较强与患者生存时间缩短相关。
结论
MACC1 可能是一种有前途的预后标志物和人类神经胶质瘤治疗的新靶点。
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