Differential induction of glioblastoma migration and growth by two forms of pleiotrophin
Differential induction of glioblastoma migration and growth by two forms of pleiotrophin
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DOI：
10.1074/jbc.m502614200
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发表时间：
2005-07-22
影响因子：
4.8
通讯作者：
Mischel, PS
中科院分区：
文献类型：
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作者：
Lu, KV;Jong, KA;Mischel, PS
胶质母细胞瘤是成人最常见的恶性脑肿瘤，也是最致命的癌症之一。分泌的生长因子多效生长因子（PTN）促进胶质母细胞瘤迁移和增殖，分别通过两种细胞表面受体（蛋白酪氨酸磷酸酶受体ζ（PTPRZ 1）和间变性淋巴瘤激酶（ALK））启动其致癌活性。在这里，我们报告的存在和纯化的两种天然形式的PTN（18和15 kDa），差异促进胶质母细胞瘤迁移和增殖。使用一组胶质母细胞瘤细胞系，包括低传代患者来源的培养物，我们证明了PTN 15以ALK依赖的方式促进胶质母细胞瘤增殖，而固定化的PTN 18以PTPRZ 1依赖的方式促进胶质母细胞瘤细胞的趋触性迁移。质谱分析表明，PTN 15与PTN 18的不同之处在于加工了12个C-末端氨基酸。为了证明临床相关性，我们显示，PTN 15，PTN 18和PTPRZ 1显着过表达胶质母细胞瘤相对于正常的大脑在mRNA和蛋白质水平上使用微阵列，蛋白质印迹和组织微阵列分析人类肿瘤。这些结果表明，PTN 18-PTPRZ 1和PTN 15-ALK信号通路代表了胶质母细胞瘤侵袭和生长的潜在重要治疗靶点。
Glioblastoma is the most common malignant brain tumor of adults and one of the most lethal cancers. The secreted growth factor pleiotrophin (PTN) promotes glioblastoma migration and proliferation, initiating its oncogenic activities through two cell surface receptors, the protein tyrosine phosphatase receptor zeta (PTPRZ1) and the anaplastic lymphoma kinase (ALK), respectively. Here, we report on the presence and purification of two naturally occurring forms of PTN ( 18 and 15 kDa) that differentially promote glioblastoma migration and proliferation. Using a panel of glioblastoma cell lines, including low passage patient-derived cultures, we demonstrate that PTN15 promotes glioblastoma proliferation in an ALK-dependent fashion, whereas immobilized PTN18 promotes haptotactic migration of glioblastoma cells in a PTPRZ1-dependent fashion. Mass spectrometric analysis indicated that PTN15 differs from PTN18 by processing of 12 C-terminal amino acids. To demonstrate clinical relevance, we show that PTN15, PTN18, and PTPRZ1 are significantly overexpressed in glioblastoma relative to normal brain at both mRNA and protein levels using microarray, Western blot, and tissue microarray analyses on human tumors. These results indicate that the PTN18-PTPRZ1 and the PTN15-ALK signaling pathways represent potentially important therapeutic targets for glioblastoma invasion and growth.