title: Fluid shear promotes chondrosarcoma cell invasion by activating matrix metalloproteinase 12 via IGF-2 and VEGF signaling pathways.
abstract: 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.
authors.affiliation: College of Life and Health Sciences, Northeastern University, Shenyang, P.R. China.|Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: P
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA.|Johns Hopkins Physical Sciences-Oncology Center, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: S-H
authors.initials: SH
authors.lastname: Chen
authors.affiliation: Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA.|Center of Cancer Nanotechonology Excellence, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: W-C
authors.initials: WC
authors.lastname: Hung
authors.affiliation: Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA.|Johns Hopkins Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: C
authors.initials: C
authors.lastname: Paul
authors.affiliation: Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: F
authors.initials: F
authors.lastname: Zhu
authors.affiliation: College of Life and Health Sciences, Northeastern University, Shenyang, P.R. China.|Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: P-P
authors.initials: PP
authors.lastname: Guan
authors.affiliation: Department of Molecular and Comparative Pathobiology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Huso
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA.|Marlene and Stewart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kontrogianni-Konstantopoulos
authors.affiliation: Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD, USA.|Johns Hopkins Physical Sciences-Oncology Center, The Johns Hopkins University, Baltimore, MD, USA.|Center of Cancer Nanotechonology Excellence, The Johns Hopkins University, Baltimore, MD, USA.|Johns Hopkins Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD, USA.|Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, MD, USA.
authors.forename: K
authors.initials: K
authors.lastname: Konstantopoulos
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D001859:Bone Neoplasms / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D002813:Chondrosarcoma / Q000201:enzymology* / Q000556:secondary; D004789:Enzyme Activation; D004790:Enzyme Induction; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000502:physiology*; D008175:Lung Neoplasms / Q000201:enzymology* / Q000556:secondary; D020935:MAP Kinase Signaling System; D053508:Matrix Metalloproteinase 12 / Q000378:metabolism*; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D042561:Vascular Endothelial Growth Factor B / Q000378:metabolism*; D042643:Vascular Endothelial Growth Factor D / Q000378:metabolism*
chemical_list: C467485:VEGFB protein, human; C579459:VEGFD protein, human; D042561:Vascular Endothelial Growth Factor B; D042643:Vascular Endothelial Growth Factor D; D007335:Insulin-Like Growth Factor II; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12