701. KSHV-initiated notch activation leads to membrane-type-1 matrix metalloproteinase-dependent lymphatic endothelial-to-mesenchymal transition.
- Author
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Cheng F, Pekkonen P, Laurinavicius S, Sugiyama N, Henderson S, Günther T, Rantanen V, Kaivanto E, Aavikko M, Sarek G, Hautaniemi S, Biberfeld P, Aaltonen L, Grundhoff A, Boshoff C, Alitalo K, Lehti K, and Ojala PM
- Subjects
- Cell Line, Endothelial Cells cytology, Endothelial Cells enzymology, Endothelial Cells virology, Gene Expression Regulation, Viral, Herpesvirus 8, Human genetics, Humans, Mesenchymal Stem Cells cytology, Mesenchymal Stem Cells enzymology, Mesenchymal Stem Cells virology, Sarcoma, Kaposi metabolism, Sarcoma, Kaposi virology, Signal Transduction, Viral Proteins genetics, Viral Proteins metabolism, Epithelial-Mesenchymal Transition, Herpesvirus 8, Human physiology, Matrix Metalloproteinase 14 metabolism, Receptors, Notch metabolism, Sarcoma, Kaposi enzymology, Sarcoma, Kaposi physiopathology
- Abstract
Kaposi sarcoma (KS), an angioproliferative disease associated with Kaposi sarcoma herpesvirus (KSHV) infection, harbors a diversity of cell types ranging from endothelial to mesenchymal cells of unclear origin. We developed a three-dimensional cell model for KSHV infection and used it to demonstrate that KSHV induces transcriptional reprogramming of lymphatic endothelial cells to mesenchymal cells via endothelial-to-mesenchymal transition (EndMT). KSHV-induced EndMT was initiated by the viral proteins vFLIP and vGPCR through Notch pathway activation, leading to gain of membrane-type-1 matrix metalloproteinase (MT1-MMP)-dependent invasive properties and concomitant changes in viral gene expression. Mesenchymal markers and MT1-MMP were found codistributed with a KSHV marker in the same cells from primary KS biopsies. Our data explain the heterogeneity of cell types within KS lesions and suggest that KSHV-induced EndMT may contribute to KS development by giving rise to infected, invasive cells while providing the virus a permissive cellular microenvironment for efficient spread., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
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