Held-Feindt Janka, Lütjohann Björn, Ungefroren Hendrik, Mehdorn Hubertus M, Mentlein Rolf
Department of Neurosurgery, University of Kiel, Kiel, Germany.
J Neurooncol. 2003 Jun;63(2):117-27. doi: 10.1023/a:1023943405292.
Gliomas are characterized by a deregulation of growth factor production and growth factor receptors expression, e.g. overproduction of the cytokine transforming growth factor-beta (TGF-beta) and overexpression/constitutive activation of receptors for the epidermal growth factor (EGF). Potential interactions of such growth factors and their signaling cascades could enhance the malignancy of these tumors. Therefore, we investigated the effects of TGF-beta and EGF alone and in combination on the proliferation of glioma cells cultivated from eight solid human WHO grade IV gliomas and one glioma cell line, analyzed the expression and intactness of the TGF-beta-signaling molecules Samd-4 and -2, and the phosphorylation of the EGF-signaling kinases ERK 1/2. The effects were divergent and complex: Whereas EGF mostly stimulated glioma cell proliferation, TGF-beta either enhanced, inhibited or had no significant effect on proliferation. In combination, co-stimulation and inhibition of the EGF-induced mitogenic activity could be observed. Smad-4/-2 were expressed in all glioma cells, one point mutation at base 1595 in Smad-4 did not affect its protein sequence. In part of the glioma cells, reduced phosphorylation of ERK 1/2 and expression of cyclin-dependent kinase inhibitor 1 or p21 was observed in co-stimulation experiments. These experiments show that TGF-beta can inhibit EGF-mediated effects only in some gliomas, whereas it enhances it in others. The interaction of both factors is very complex and varies between different gliomas.
胶质瘤的特征在于生长因子产生失调和生长因子受体表达异常，例如细胞因子转化生长因子-β（TGF-β）过度产生以及表皮生长因子（EGF）受体过度表达/组成性激活。此类生长因子及其信号级联的潜在相互作用可能会增强这些肿瘤的恶性程度。因此，我们研究了单独及联合使用TGF-β和EGF对源自8例WHO IV级实体性人类胶质瘤和1个胶质瘤细胞系的胶质瘤细胞增殖的影响，分析了TGF-β信号分子Samd-4和-2的表达及完整性，以及EGF信号激酶ERK 1/2的磷酸化情况。这些影响是多样且复杂的：EGF大多刺激胶质瘤细胞增殖，而TGF-β对增殖的影响则是增强、抑制或无显著作用。联合使用时，可观察到对EGF诱导的促有丝分裂活性的协同刺激和抑制作用。所有胶质瘤细胞均表达Smad-4/-2，Smad-4第1595位碱基处的一个点突变不影响其蛋白质序列。在协同刺激实验中，部分胶质瘤细胞中观察到ERK 1/2磷酸化降低以及细胞周期蛋白依赖性激酶抑制剂1或p21表达降低。这些实验表明，TGF-β仅在某些胶质瘤中可抑制EGF介导的效应，而在其他胶质瘤中则增强该效应。两种因子之间的相互作用非常复杂，且在不同胶质瘤之间存在差异。
