Glioblastoma is a highly vascularized brain tumor, and antiangiogenic therapy improves its progression-free survival. However, current antiangiogenic therapy induces serious adverse effects including neuronal cytotoxicity and tumor invasiveness and resistance to therapy. Although it has been suggested that the physical microenvironment has a key role in tumor angiogenesis and progression, the mechanism by which physical properties of extracellular matrix control tumor angiogenesis and glioblastoma progression is not completely understood. Herein we show that physical compaction (the process in which cells gather and pack together and cause associated changes in cell shape and size) of human glioblastoma cell lines U87MG, U251, and LN229 induces expression of collagen types IV and VI and the collagen crosslinking enzyme lysyl oxidase and up-regulates in vitro expression of the angiogenic factor vascular endothelial growth factor. The lysyl oxidase inhibitor β-aminopropionitrile disrupts collagen structure in the tumor and inhibits tumor angiogenesis and glioblastoma multiforme growth in a mouse orthotopic brain tumor model. Similarly, d-penicillamine, which inhibits lysyl oxidase enzymatic activity by depleting intracerebral copper, also exhibits antiangiogenic effects on brain tumor growth in mice. These findings suggest that tumor microenvironment controlled by collagen structure is important in tumor angiogenesis and brain tumor progression.

译文

胶质母细胞瘤是一种高度血管化的脑肿瘤,抗血管生成治疗可改善其无进展生存期。然而,当前的抗血管生成疗法会引起严重的不良反应,包括神经元细胞毒性,肿瘤侵袭性和对治疗的抵抗力。尽管已经提出物理微环境在肿瘤血管生成和进展中起关键作用,但细胞外基质的物理特性控制肿瘤血管生成和胶质母细胞瘤进展的机制尚不完全清楚。在本文中,我们显示了人胶质母细胞瘤细胞系U87MG,U251的物理压实 (细胞聚集并聚集在一起并引起细胞形状和大小相关变化的过程),LN229诱导 ⅳ 型和 ⅵ 型胶原和胶原交联酶赖氨酰氧化酶的表达,并上调血管生成因子血管内皮生长因子的体外表达。在小鼠原位脑肿瘤模型中,赖氨酰氧化酶抑制剂 β-氨基丙腈破坏肿瘤中的胶原蛋白结构并抑制肿瘤血管生成和多形性胶质母细胞瘤的生长。同样,d-青霉胺通过消耗脑内铜来抑制赖氨酰氧化酶的酶活性,也对小鼠脑肿瘤生长表现出抗血管生成作用。这些发现表明,胶原结构控制的肿瘤微环境在肿瘤血管生成和脑肿瘤进展中很重要。

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