title: Kaposi's sarcoma-associated herpesvirus downregulates transforming growth factor β2 to promote enhanced stability of capillary-like tube formation.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS), the most common tumor of AIDS patients worldwide. A key characteristic of KS tumors is extremely high levels of vascular slits and extravasated red blood cells, making neoangiogenesis a key component of the tumor. The main KS tumor cell is the spindle cell, a cell of endothelial origin that maintains KSHV predominantly in the latent state. In cultured endothelial cells, latent KSHV infection induces angiogenic phenotypes, including longer-term stabilization of capillary-like tube formation in Matrigel, a basement membrane matrix. The present studies show that KSHV infection of endothelial cells strongly downregulates transforming growth factor β2 (TGF-β2). This downregulation allows the stabilization of capillary-like tube formation during latent infection, as the addition of exogenous TGF-β2 inhibits the KSHV-induced stability of these structures. While two KSHV microRNAs are sufficient to downregulate TGF-β2 in endothelial cells, they are not required during KSHV infection. However, activation of the gp130 cell surface receptor is both necessary and sufficient for downregulation of TGF-β2 in KSHV-infected cells.
  
  
  OBJECTIVE
  Kaposi's sarcoma is a highly vascularized, endothelial cell-based tumor supporting large amounts of angiogenesis. There is evidence that KSHV, the etiologic agent of KS, induces aberrant angiogenesis. For example, KSHV induces stabilization of capillary-like tube formation in cultured endothelial cells. A clearer understanding of how KSHV regulates angiogenesis could provide potential therapeutic targets for KS. We found that KSHV downregulates TGF-β2, a cytokine related to TGF-β1 that is known to inhibit angiogenesis. The downregulation of this inhibitor promotes the stability of capillary-like tube formation insofar as adding back TGF-β2 to infected cells blocks KSHV-induced long-term tubule stability. Therefore, KSHV downregulation of TGF-β2 may increase aberrant vascularization in KS tumors through increased capillary formation and thereby aid in KS tumor promotion.
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, USA.
authors.forename: Terri A
authors.initials: TA
authors.lastname: DiMaio
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, USA.
authors.forename: Kimberley D
authors.initials: KD
authors.lastname: Gutierrez
authors.affiliation: Department of Microbiology, University of Washington, Seattle, Washington, USA Lagunoff@u.washington.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Lagunoff
mesh_terms: D002460:Cell Line; D050822:Cytokine Receptor gp130 / Q000096:biosynthesis; D042783:Endothelial Cells / Q000502:physiology* / Q000821:virology*; D019288:Herpesvirus 8, Human / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D009389:Neovascularization, Pathologic; D053781:Transforming Growth Factor beta2 / Q000037:antagonists & inhibitors*
chemical_list: C494199:IL6ST protein, human; D053781:Transforming Growth Factor beta2; D050822:Cytokine Receptor gp130