Aberrant Expression of Retinoic Acid Signaling Molecules Influences Patient Survival in Astrocytic Gliomas
Aberrant Expression of Retinoic Acid Signaling Molecules Influences Patient Survival in Astrocytic Gliomas
复制标题
DOI：
10.1016/j.ajpath.2011.01.051
复制
发表时间：
2011-05-01
影响因子：
6
通讯作者：
Herold-Mende, Christel
中科院分区：
文献类型：
--
作者：
Campos, Benito;Centner, Franz-Simon;Herold-Mende, Christel
未分化细胞群可能影响恶性胶质瘤的肿瘤生长。我们研究了维甲酸（RA）分化途径的潜在中断，可能导致分化能力丧失，影响患者预后。在283例星形胶质细胞瘤中分析了属于RA分化途径的关键分子的表达，并与肿瘤增殖、肿瘤分化和患者生存相关。此外，在原位浓度的类维生素A在肿瘤中进行了测量，并在体外研究RA信号转导事件。与其他肿瘤不同，在胶质瘤中，大多数RA信号分子的表达随着恶性程度的增加而增加，并且与高级别胶质瘤中肿瘤内类维生素A水平的增加有关。异常表达的RA信号分子包括i）视黄醇结合蛋白CRBP 1，其促进细胞类维生素A摄取; ii）ALDH 1A 1，其能够激活RA前体; iii）RA降解酶CYP 26 B1;和iv）RA结合蛋白FABP 5，其可以抑制RA诱导的分化。相比之下，促进分化的RA结合蛋白CRABP 2的表达在高级别肿瘤中减少。此外，CRBP 1的表达与肿瘤增殖相关，FABP 5的表达与未分化肿瘤表型相关。CRBP 1和ALDH 1A 1是不良患者生存的独立预后标志物。我们的数据表明，RA信号的复杂和临床相关的失调，这似乎是神经胶质瘤发病机制中的一个中心事件。(Am J Pathol 2011，178：1953-1964; DOI：10.1016/j.ajpath.2011.01.051）
Undifferentiated cell populations may influence tumor growth in malignant glioma. We investigated potential disruptions in the retinoic acid (RA) differentiation pathway that could lead to a loss of differentiation capacity, influencing patient prognosis. Expression of key molecules belonging to the RA differentiation pathway was analyzed in 283 astrocytic gliomas and was correlated with tumor proliferation, tumor differentiation, and patient survival. In addition, in situ concentrations of retinoids were measured in tumors, and RA signaling events were studied in vitro. Unlike other tumors, in gliomas expression of most RA signaling molecules increased with malignancy and was associated with augmented intratumoral retinoid levels in high-grade gliomas. Aberrantly expressed RA signaling molecules included i) the retinol-binding protein CRBP1, which facilitates cellular retinoid uptake; ii) ALDH1A1, capable of activating RA precursors; iii) the RA-degrading enzyme CYP26B1; and iv) the RA-binding protein FABP5, which can inhibit RA-induced differentiation. In contrast, expression of the RA-binding protein CRABP2, which fosters differentiation, was decreased in high-grade tumors. Moreover, expression of CRBP1 correlated with tumor proliferation, and FABP5 expression correlated with an undifferentiated tumor phenotype. CRBP1 and ALDH1A1 were independent prognostic markers for adverse patient survival. Our data indicate a complex and clinically relevant deregulation of RA signaling, which seems to be a central event in glioma pathogenesis. (Am J Pathol 2011, 178:1953-1964; DOI: 10.1016/j.ajpath.2011.01.051)