GM-CSF enhances tumor invasion by elevated MMP-2, -9, and -26 expression.
GM-CSF enhances tumor invasion by elevated MMP-2, -9, and -26 expression.
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DOI：
10.1002/cam4.20
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发表时间：
2013-04
期刊：
影响因子：
4
通讯作者：
Mueller, Margareta M.
中科院分区：
文献类型：
--
作者：
Gutschalk, Claudia M.;Yanamandra, Archana K.;Linde, Nina;Meides, Alice;Depner, Sofia;Mueller, Margareta M.
粒细胞-巨噬细胞集落刺激因子（GM-CSF）以自分泌和旁分泌的方式促进不同肿瘤模型中的肿瘤进展。然而，同时 GM-CSF 也用于癌症治疗，以改善中性粒细胞减少症。我们之前已经在 GM-CSF 和 G-CSF 表达或阴性皮肤或头颈鳞状细胞癌中证明，GM-CSF 表达与高度血管生成和侵袭性肿瘤表型相关。为了确定 GM-CSF 对肿瘤侵袭的功能贡献，我们用 GM-CSF 稳定转染 GM-CSF 阴性结肠腺癌细胞系 HT-29 或用外源 GM-CSF 处理相同的细胞系。虽然 GM-CSF 过表达和治疗分别在体外和体内减少了肿瘤细胞增殖和肿瘤生长，但它促进了肿瘤进展。连同体外迁移能力的增强，我们观察到在 GM-CSF 过表达或 GM-CSF 治疗的肿瘤中，随着诱导激活的肿瘤基质，肿瘤细胞侵入周围组织的速度显着增加。在复杂的 3D 体外模型中，GM-CSF 表达增强与基底膜沉积中断相关，这可能是由 MMP-2、-9 和 -26 表达和激活增加介导的。 GM-CSF 阻断抗体治疗逆转了这种效应。这些肿瘤细胞来源的蛋白酶的存在和活性的增加在体内得到证实。这里，MMP-26蛋白的表达主要位于侵袭前和早期侵袭区域，表明MMP-26表达是促进GM-CSF依赖性肿瘤侵袭的早期事件。
Granulocyte–macrophage colony-stimulating factor (GM-CSF) promotes tumor progression in different tumor models in an autocrine and paracrine manner. However, at the same time GM-CSF is used in cancer therapies to ameliorate neutropenia. We have previously shown in GM-CSF and G-CSF expressing or negative skin or head and neck squamous cell carcinoma that GM-CSF expression is associated with a highly angiogenic and invasive tumor phenotype. To determine the functional contribution of GM-CSF to tumor invasion, we stably transfected a GM-CSF negative colon adenocarcinoma cell line HT-29 with GM-CSF or treated the same cell line with exogenous GM-CSF. While GM-CSF overexpression and treatment reduced tumor cell proliferation and tumor growth in vitro and in vivo, respectively, it contributed to tumor progression. Together with an enhanced migratory capacity in vitro, we observed a striking increase in tumor cell invasion into the surrounding tissue concomitant with the induction of an activated tumor stroma in GM-CSF overexpressing or GM-CSF treated tumors. In a complex 3D in vitro model, enhanced GM-CSF expression was associated with a discontinued basement membrane deposition that might be mediated by the increased expression and activation of MMP-2, -9, and -26. Treatment with GM-CSF blocking antibodies reversed this effect. The increased presence and activity of these tumor cell derived proteases was confirmed in vivo. Here, expression of MMP-26 protein was predominantly located in pre- and early-invasive areas suggesting MMP-26 expression as an early event in promoting GM-CSF dependent tumor invasion.
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影响因子：
4.8
作者：
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通讯作者：
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作者：
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通讯作者：
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影响因子：
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