The autocrine loop of TGF-α/EGFR and brain tumors
The autocrine loop of TGF-α/EGFR and brain tumors
复制标题
DOI：
10.1023/a:1005824802617
复制
发表时间：
1997-12-01
影响因子：
3.9
通讯作者：
Yung, WKA
中科院分区：
文献类型：
--
作者：
Tang, P;Steck, PA;Yung, WKA
人类恶性胶质瘤是中枢神经系统原发性肿瘤最常见的形式。由于其位置和侵入性，迄今为止的治疗主要是姑息治疗。因此，了解肿瘤转化和进展的分子细节对于制定针对这种胎儿肿瘤的有效治疗策略至关重要。在这些肿瘤中发现的基因改变中，p53失活和PDGF/PDGFR激活代表早期事件，而10号染色体的丢失和EGFR基因扩增和重排代表晚期事件。对神经胶质瘤细胞系和原发性肿瘤组织的研究强烈表明，TGF-α和EGFR作为支持人类神经胶质瘤增殖的重要自分泌环，特别是在高级神经胶质瘤中，因为在这些高级肿瘤中也发现了TGF-α表达升高。此外，反义构建体下调TGF-α的表达已被证明可以抑制包括神经胶质瘤在内的几种类型的人类肿瘤细胞生长。使用该自分泌环作为靶点的其他治疗方法还包括使用单克隆抗体及其细胞毒性偶联物。最近，人们对 EGFR 介导的信号转导途径有了相当多的了解，其中包括 GRB2/mSOS1 介导的 MAP 激酶激活； JAK/STATs 途径、PLC-gamma 途径。然而，在将这些途径的特定组成部分应用于临床上有效控制肿瘤生长之前，仍然需要做很多工作。
Malignant human gliomas are the most common forms of primary tumors in the central nerve system. Due to their location and invasive nature, treatment so far has been mainly palliative. Thus, understanding the molecular detail of tumor transformation and progression is crucial for developing effective therapeutic strategy for this fetal tumor. Among the genetic alternations found in these tumors, p53 inactivation and PDGF/PDGFR activation represent the early events, and the loss of chromosome 10 and gene amplification and rearrangement of EGFR represent the late events. Studies with both glioma cell lines and primary tumor tissues have strongly suggested that TGF-alpha and EGFR function as an important autocrine loop in supporting proliferation of human glioma, especially in high grade glioma, since elevated TGF-alpha expression is also found in these high grade tumors. Furthermore, down regulation of the expression of TGF-alpha by antisense constructs has been shown to inhibit several types of human tumor cell growth including glioma. Other means of therapeutic approaches using this autocrine loop as a target also include the use of monoclonal antibodies and their cytotoxic conjugated. Considerable understanding of the EGFR-mediated signal transduction pathways has become available recently, which including GRB2/mSOS1 mediated MAP kinase activation; JAK/STATs pathway, PLC-gamma pathway. However, much work still needs to be done before a specific component of these pathways can be applied for effective control of tumor growth in the clinic.