Enforced expression of tissue inhibitor of matrix metalloproteinase-3 affects functional capillary morphogenesis and inhibits tumor growth in a murine tumor model
Enforced expression of tissue inhibitor of matrix metalloproteinase-3 affects functional capillary morphogenesis and inhibits tumor growth in a murine tumor model
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DOI：
10.1182/blood.v100.9.3361
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发表时间：
2002-11-01
期刊：
影响因子：
20.3
通讯作者：
Davidoff, AM
中科院分区：
文献类型：
--
作者：
Spurbeck, WW;Ng, CYC;Davidoff, AM
细胞外基质的动态平衡是降解和重塑之间的微妙平衡，这种平衡是通过激活的基质金属蛋白酶(MMPs)和特定的基质金属蛋白酶组织抑制物(TIMPs)相互作用来维持的。基质金属蛋白酶活性的上调，有利于基底膜和细胞外基质的蛋白降解，与肿瘤的生长和转移以及肿瘤相关血管的形成有关，而抑制基质金属蛋白酶活性似乎限制了这些过程。我们利用逆转录病毒介导的基因传递技术在小鼠神经母细胞瘤和黑色素瘤细胞中持续自分泌表达TIMP-3，以进一步检测TIMP-3在体内抑制血管生成的能力。与对照组相比，严重联合免疫缺陷(SCID)小鼠的两种组织学类型的基因修饰的肿瘤细胞的生长都受到显著的限制。大体上，这些肿瘤很小，几乎没有供血的血管。组织学评估显示，尽管过度表达TIMP-3的肿瘤中CD31(+)内皮细胞数量增加，但这些内皮细胞并未形成功能性小管，这是血管连续性降低和周细胞募集最少的证据。在体外实验和TIMP-3过表达的肿瘤中，这种作用似乎部分是通过在存在TIMP-3的情况下内皮细胞减少血管内皮细胞(VE)-钙粘附素的表达来实现的。综上所述，这些结果表明，过表达TIMP-3可以抑制血管生成和相关的肿瘤生长，并且TIMP-3的抗血管生成作用似乎是通过抑制功能性毛细血管形态发生来实现的。
Homeostasis of the extracellular matrix is a delicate balance between degradation and remodeling, the balance being maintained by the interaction of activated matrix metalloproteinases (MMPs) and specific tissue inhibitors of matrix metalloproteinases (TIMPs). Up-regulation of MMP activity, favoring proteolytic degradation of the basement membrane and extracellular matrix, has been linked to tumor growth and metastasis, as well as tumor-associated anglogenesis, whereas inhibition of MMP activity appears to restrict these processes. We have used retroviral-mediated gene delivery to effect sustained autocrine expression of TIMP-3 in murine neuroblastoma and melanoma tumor cells in order to further examine the ability of TIMPs to inhibit angiogenesis in vivo. Growth of both histologic, types of gene-modified tumor cells in severe combined immunodeficiency (SCID) mice was significantly restricted when compared with controls. Grossly, these tumors were small and had few feeding vessels. Histologic evaluation revealed that although tumors overexpressing TIMP-3 had an increased number of CD31(+) endothelial cells, these endothelial cells had not formed functional tubules, as evidenced by decreased vessel continuity and minimal pericyte recruitment. This effect appears to be mediated, in part, by decreased expression of vascular endothelial (VE)-cadherin by endothelial cells in the presence of TIMP-3 as seen both in an in vitro assay and in TIMP-3-overexpressing tumors. Taken together, these results demonstrate that overexpression of TIMP-3 can inhibit angiogenesis and associated tumor growth, and that the antiangiogenic effects of TIMP-3 appear to be mediated through the inhibition of functional capillary morphogenesis.