Heparanase-induced shedding of syndecan-1/CD138 in myeloma and endothelial cells activates VEGFR2 and an invasive phenotype: prevention by novel synstatins.
Heparanase-induced shedding of syndecan-1/CD138 in myeloma and endothelial cells activates VEGFR2 and an invasive phenotype: prevention by novel synstatins.
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肝素酶诱导的骨髓瘤和内皮细胞中Syndecan-1/CD138的脱落会激活VEGFR2和侵入性表型：新型合成蛋白预防。
DOI：
10.1038/oncsis.2016.5
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发表时间：
2016-02-29
期刊：
影响因子：
6.2
通讯作者：
Rapraeger, A. C.
中科院分区：
文献类型：
--
作者：
Jung, O.;Trapp-Stamborski, V.;Purushothaman, A.;Jin, H.;Wang, H.;Sanderson, R. D.;Rapraeger, A. C.
当恶性浆细胞侵入骨髓并在骨髓中形成多发性肿瘤时，多发性骨髓瘤就会发生。高水平的乙酰肝素酶（HPSE）与骨髓瘤患者的不良预后相关。这种酶的一个可能的靶点是硫酸乙酰肝素（HS）蛋白聚糖多配体蛋白聚糖-1（Sdc 1，CD 138），它在骨髓瘤细胞上高度表达，导致这种疾病的预后不良。我们发现HPSE促进骨髓瘤细胞中由极晚期抗原4（VLA-4或α4β1整联蛋白）介导的侵袭性表型，所述骨髓瘤细胞接种在纤连蛋白（FN）或血管内皮细胞粘附分子-1（VCAM-1）上，所述纤连蛋白或血管内皮细胞粘附分子-1（VCAM-1）是骨髓中普遍存在的配体。其表型依赖于血管内皮细胞生长因子受体2（VEGFR 2），VEGFR 2在骨髓瘤中异常表达，其特征在于高度增生的板状伪足和细胞侵袭。HPSE介导的对Sdc 1上HS的修剪和随后的基质金属蛋白酶-9介导的多配体蛋白聚糖的脱落暴露了Sdc 1中结合VEGFR 2和VLA-4的质膜位点，从而将VEGFR 2偶联至整联蛋白。Shed Sdc 1可以通过重组Sdc 1胞外域或通过基于其结合基序的肽来模拟，其导致VLA-4从迁移细胞的后缘（尾足）重新定向到前缘，与VEGFR 2偶联并激活VEGFR 2。仅含有VLA-4或VEGFR 2结合位点的肽（称为“合成抑制素”）竞争性抑制侵袭，因为它们阻断受体的偶联。这种机制也被血管内皮细胞利用，在内皮细胞管形成期间，它也被HPSE激活。总的来说，我们的研究结果首次揭示了HPSE调节Sdc 1功能以促进肿瘤细胞侵袭和血管生成，从而驱动多发性骨髓瘤进展的机制。抑制性synstatin，或HPSE酶活性抑制剂，可能显示出作为骨髓瘤外渗和扩散的治疗剂的前景。
Multiple myeloma arises when malignant plasma cells invade and form multiple tumors in the bone marrow. High levels of heparanase (HPSE) correlate with poor prognosis in myeloma patients. A likely target of the enzyme is the heparan sulfate (HS) proteoglycan syndecan-1 (Sdc1, CD138), which is highly expressed on myeloma cells and contributes to poor prognosis in this disease. We find that HPSE promotes an invasive phenotype mediated by the very late antigen-4 (VLA-4, or α4β1 integrin) in myeloma cells plated on either fibronectin (FN) or vascular endothelial cell adhesion molecule-1 (VCAM-1), ligands that are prevalent in the bone marrow. The phenotype depends on vascular endothelial cell growth factor receptor-2 (VEGFR2), which is aberrantly expressed in myeloma, and is characterized by a highly protrusive lamellipodium and cell invasion. HPSE-mediated trimming of the HS on Sdc1 and subsequent matrix metalloproteinase-9-mediated shedding of the syndecan exposes a juxtamembrane site in Sdc1 that binds VEGFR2 and VLA-4, thereby coupling VEGFR2 to the integrin. Shed Sdc1 can be mimicked by recombinant Sdc1 ectodomain or by a peptide based on its binding motif, which causes VLA-4 to re-orient from the lagging edge (uropod) to the leading edge of migrating cells, couple with and activate VEGFR2. Peptides (called 'synstatins') containing only the VLA-4 or VEGFR2 binding sites competitively inhibit invasion, as they block coupling of the receptors. This mechanism is also utilized by vascular endothelial cells, in which it is also activated by HPSE, during endothelial cell tube formation. Collectively, our findings reveal for the first time the mechanism through which HPSE modulates Sdc1 function to promote both tumor cell invasion and angiogenesis, thereby driving multiple myeloma progression. The inhibitory synstatins, or inhibitors of HPSE enzyme activity, are likely to show promise as therapeutics against myeloma extravasation and spread.
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影响因子：
3.7
作者：
Hammond, Edward;Brandt, Ralf;Dredge, Keith
通讯作者：
Dredge, Keith
影响因子：
4.8
作者：
Goldschmidt, O;Zcharia, E;Vlodavsky, I
通讯作者：
Vlodavsky, I
影响因子：
5.8
作者：
Cassinelli, G.;Lanzi, C.;Zunino, F.
通讯作者：
Zunino, F.
DOI：
10.1084/jem.20081278
发表时间：
2009-03-16
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Beauvais DM;Ell BJ;McWhorter AR;Rapraeger AC
通讯作者：
Rapraeger AC
影响因子：
11.2
作者：
Garmy-Susini B;Avraamides CJ;Schmid MC;Foubert P;Ellies LG;Barnes L;Feral C;Papayannopoulou T;Lowy A;Blair SL;Cheresh D;Ginsberg M;Varner JA
通讯作者：
Varner JA