Fibulin-2 Is a Driver of Malignant Progression in Lung Adenocarcinoma
Fibulin-2 Is a Driver of Malignant Progression in Lung Adenocarcinoma
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DOI：
10.1371/journal.pone.0067054
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发表时间：
2013-06-10
期刊：
影响因子：
3.7
通讯作者：
Kurie, Jonathan M.
中科院分区：
文献类型：
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作者：
Baird, Brandi N.;Schliekelman, Mark J.;Kurie, Jonathan M.
上皮肿瘤的细胞外基质在不受控制的生长期间经历结构重塑，产生区域异质性和扭转应力。在面对动态生物物理力时，基质的完整性如何保持在很大程度上是不确定的。在这里，我们研究了fibulin-2的作用，fibulin-2是一种基质糖蛋白，在生物力学上起着分子间卡环的作用，从而促进了超分子组装。Fibulin-2在人肺腺癌的细胞外基质中是丰富的，并且在源自小鼠的肿瘤细胞系中高度表达，所述小鼠通过突变K-ras和p53的共表达而发展成转移性肺腺癌。在肿瘤细胞中的功能丧失实验揭示，fibulin-2是肿瘤细胞在同基因小鼠中生长和转移所必需的，这是一个令人惊讶的发现，因为已知其他肿瘤内细胞类型分泌fibulin-2。然而，肿瘤细胞在Fbln 2-null和-野生型同窝仔中同样良好地生长和转移，这意味着恶性进展特异性地依赖于肿瘤细胞来源的fibulin-2，其不能被fibulin-2的其他细胞来源抵消。Fibulin-2缺陷削弱了肿瘤细胞在Boyden室中迁移和侵入的能力，在小鼠中产生坚硬的细胞外基质，交联分泌的胶原蛋白并粘附于胶原蛋白。我们得出结论，fibulin-2是肺腺癌恶性进展的驱动因素，并在胶原交联和肿瘤细胞粘附胶原中发挥意想不到的作用。
The extracellular matrix of epithelial tumors undergoes structural remodeling during periods of uncontrolled growth, creating regional heterogeneity and torsional stress. How matrix integrity is maintained in the face of dynamic biophysical forces is largely undefined. Here we investigated the role of fibulin-2, a matrix glycoprotein that functions biomechanically as an inter-molecular clasp and thereby facilitates supra-molecular assembly. Fibulin-2 was abundant in the extracellular matrix of human lung adenocarcinomas and was highly expressed in tumor cell lines derived from mice that develop metastatic lung adenocarcinoma from co-expression of mutant K-ras and p53. Loss-offunction experiments in tumor cells revealed that fibulin-2 was required for tumor cells to grow and metastasize in syngeneic mice, a surprising finding given that other intra-tumoral cell types are known to secrete fibulin-2. However, tumor cells grew and metastasized equally well in Fbln2-null and -wild-type littermates, implying that malignant progression was dependent specifically upon tumor cellderived fibulin-2, which could not be offset by other cellular sources of fibulin-2. Fibulin-2 deficiency impaired the ability of tumor cells to migrate and invade in Boyden chambers, to create a stiff extracellular matrix in mice, to cross-link secreted collagen, and to adhere to collagen. We conclude that fibulin-2 is a driver of malignant progression in lung adenocarcinoma and plays an unexpected role in collagen cross-linking and tumor cell adherence to collagen.