Fluid shear promotes chondrosarcoma cell invasion by activating matrix metalloproteinase 12 via IGF-2 and VEGF signaling pathways

• Published in: Oncogene Vol. 34; no. 35; pp. 4558 - 4569
• Main Authors: Wang, P, Chen, S-H, Hung, W-C, Paul, C, Zhu, F, Guan, P-P, Huso, D L, Kontrogianni-Konstantopoulos, A, Konstantopoulos, K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.08.2015; Nature Publishing Group
• Subjects: 1-Phosphatidylinositol 3-kinase; 101/1; 13/105; 13/51; 13/89; 14; 14/1; 14/105; 14/34; 14/63; 631/67/327; Animals; Apoptosis; Biomechanical Phenomena; Body fluids; Bone Neoplasms - enzymology; Bone Neoplasms - pathology; Cancer; Care and treatment; Cell Biology; Cell Line, Tumor; Cell Movement; Cellular biology; Cellular signal transduction; Chondrocytes; Chondrosarcoma; Chondrosarcoma - enzymology; Chondrosarcoma - secondary; Colonization; Enzyme Activation; Enzyme Induction; Fluid flow; Gene Expression Regulation, Neoplastic; Genetic aspects; Human Genetics; Humans; Insulin; Insulin-Like Growth Factor II - physiology; Insulin-like growth factors; Internal Medicine; Intracellular signalling; Kinases; Lung Neoplasms - enzymology; Lung Neoplasms - secondary; MAP Kinase Signaling System; Matrix; Matrix metalloproteinase; Matrix Metalloproteinase 12 - metabolism; Mechanical stimuli; Medicine; Medicine & Public Health; Metalloproteinase; Metastases; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Molecular modelling; Neoplasm Invasiveness; Neoplasm Transplantation; Oncology; original-article; Physiological aspects; Risk factors; Shear stress; Signal transduction; Vascular endothelial growth factor; Vascular Endothelial Growth Factor B - metabolism; Vascular Endothelial Growth Factor D - metabolism; United States
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.397

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/cm 2 ) 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.