Ulbricht Ulrike, Brockmann Marc A, Aigner Achim, Eckerich Carmen, Müller Sabine, Fillbrandt Regina, Westphal Manfred, Lamszus Katrin
Department of Neurosurgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
J Neuropathol Exp Neurol. 2003 Dec;62(12):1265-75. doi: 10.1093/jnen/62.12.1265.
Using subtractive cloning combined with cDNA array analysis, we previously identified the genes encoding for the protein tyrosine phosphatase zeta/receptor-type protein tyrosine phosphatase beta (PTPzeta/RPTPbeta) and its ligand pleiotrophin (PTN) as overexpressed in human glioblastomas compared to normal brain. Both molecules have been implicated in neuronal migration during central nervous system development, and PTN is known to be involved in tumor growth and angiogenesis. We confirm overexpression of both molecules at the protein level in astrocytic gliomas of different malignancy grades. PTPzeta/RPTPbeta immunoreactivity was associated with increasing malignancy grade and localized predominantly to the tumor cells. PTN immunoreactivity as determined by ELISA and immunohistochemistry analysis was increased in low-grade astrocytomas compared to normal brain. Further increase in malignant gliomas was marginal, and thus no correlation with malignancy grade or microvessel density was present. However, PTN levels were significantly associated with those of fibroblast growth factor-2, suggesting co-regulation of both factors. Functionally, PTN induced weak chemotactic and strong haptotactic migration of glioblastoma and cerebral microvascular endothelial cells. Haptotaxis of glioblastoma cells towards PTN was specifically inhibited by an anti-PTPzeta/RPTPbeta antibody. Our findings suggest that upregulated expression of PTN and PTPzeta/RPTPbeta in human astrocytic tumor cells can create an autocrine loop that is important for glioma cell migration. Although PTN is a secreted growth factor, it appears to exert its mitogenic effects mostly in a matrix-immobilized form, serving as a substrate for migrating tumor cells.
利用消减克隆技术结合cDNA阵列分析，我们先前发现，与正常脑组织相比，编码蛋白酪氨酸磷酸酶ζ/受体型蛋白酪氨酸磷酸酶β（PTPζ/RPTPβ）及其配体多效生长因子（PTN）的基因在人类胶质母细胞瘤中过表达。这两种分子都与中枢神经系统发育过程中的神经元迁移有关，并且已知PTN参与肿瘤生长和血管生成。我们证实在不同恶性程度的星形细胞瘤中，这两种分子在蛋白水平均过表达。PTPζ/RPTPβ免疫反应性与恶性程度增加相关，且主要定位于肿瘤细胞。通过酶联免疫吸附测定（ELISA）和免疫组织化学分析确定，与正常脑组织相比，低级别星形细胞瘤中的PTN免疫反应性增加。恶性胶质瘤中的进一步增加不明显，因此与恶性程度或微血管密度不存在相关性。然而，PTN水平与成纤维细胞生长因子-2的水平显著相关，提示这两种因子存在共同调节。在功能上，PTN诱导胶质母细胞瘤和脑微血管内皮细胞发生弱趋化性和强趋触性迁移。抗PTPζ/RPTPβ抗体可特异性抑制胶质母细胞瘤细胞对PTN的趋触性。我们的研究结果表明，人类星形细胞瘤细胞中PTN和PTPζ/RPTPβ的上调表达可形成一个自分泌环，这对胶质瘤细胞迁移很重要。尽管PTN是一种分泌型生长因子，但其促有丝分裂作用似乎主要以基质固定形式发挥，作为迁移肿瘤细胞的底物。
