Fluid shear promotes chondrosarcoma cell invasion by activating matrix metalloproteinase 12 via IGF-2 and VEGF signaling pathways.
Fluid shear promotes chondrosarcoma cell invasion by activating matrix metalloproteinase 12 via IGF-2 and VEGF signaling pathways.
复制标题
流体剪切通过 IGF-2 和 VEGF 信号通路激活基质金属蛋白酶 12，从而促进软骨肉瘤细胞侵袭。
作者：
Interstitial fluid flow in and around the tumor tissue is a physiologically relevant mechanical signal that regulates intracellular signaling pathways throughout the tumor. Yet, the effects of interstitial flow and associated fluid shear stress on the tumor cell function have been largely overlooked. Using in vitro bioengineering models in conjunction with molecular cell biology tools, we found that fluid shear (2 dyn/cm2) markedly upregulates matrix metalloproteinase 12 (MMP-12) expression and its activity in human chondrosarcoma cells. MMP-12 expression is induced in human chondrocytes during malignant transformation. However, the signaling pathway regulating MMP-12 expression and its potential role in human chondrosarcoma cell invasion and metastasis have yet to be delineated. We discovered that fluid shear stress induces the synthesis of insulin growth factor-2 (IGF-2) and vascular endothelial growth factor (VEGF) B and D, which in turn transactivate MMP-12 via PI3-K, p38 and JNK signaling pathways. IGF-2-, VEGF-B- or VEGF-D-stimulated chondrosarcoma cells display markedly higher migratory and invasive potentials in vitro, which are blocked by inhibiting MMP-12, PI3-K, p38 or JNK activity. Moreover, recombinant human MMP-12 or MMP-12 overexpression can potentiate chondrosarcoma cell invasion in vitro and the lung colonization in vivo. By reconstructing and delineating the signaling pathway regulating MMP-12 activation, potential therapeutic strategies that interfere with chondrosarcoma cell invasion may be identified.
登录
查看更多内容
影响因子：
3.1
作者：
Cheng, Peng;Jiang, Fo Hu;Zhang, Yan Jie
通讯作者：
Zhang, Yan Jie
影响因子：
7.8
作者：
Orr, A Wayne;Sanders, John M;Bevard, Melissa;Coleman, Elizabeth;Sarembock, Ian J;Schwartz, Martin Alexander
通讯作者：
Schwartz, Martin Alexander
影响因子：
4.6
作者：
Chen SH;Hung WC;Wang P;Paul C;Konstantopoulos K
通讯作者：
Konstantopoulos K
影响因子：
4
作者：
dela Paz, Nathaniel G.;Walshe, Tony E.;D'Amore, Patricia A.
通讯作者：
D'Amore, Patricia A.
影响因子：
4.8
作者：
Balzer, Eric M.;Tong, Ziqiu;Konstantopoulos, Konstantinos
通讯作者：
Konstantopoulos, Konstantinos