title: INK4a/ARF [corrected] inactivation with activation of the NF-κB/IL-6 pathway is sufficient to drive the development and growth of angiosarcoma.
abstract: Although human angiosarcoma has been associated frequently with mutational inactivation of the tumor suppressor gene Ink4a/Arf, the underlying mechanisms have not been delineated. Here we report that malignant angiosarcoma is associated with high levels of RelA/NF-κB and IL-6 in contrast to normal vessels or benign hemagiomas. Studies of Ink4a/Arf deficient mice not only recapitulate genetic traits observed in human angiosarcoma, but also unveil a possible therapeutic link comprised of the NF-kB/IL-6/Stat3 signaling axis. In Ink4a/Arf(-/-) cells, NF-κB controlled Stat3 signaling by transcriptionally controlling the expression of IL-6, gp130, and Jak2. Further, IL-6 mediated Stat3 signaling through the sIL-6R. Inhibition of Ikkβ solely in myeloid cells was insufficient to block angiosarcoma development; in contrast, systemic inhibition of Ikkβ, IL-6, or Stat3 markedly inhibited angiosarcoma growth. Our findings offer clinical implications for targeting the NF-kB/IL-6/STAT3 pathway as a rational strategy to treat angiosarcoma.
authors: Veterans Affairs Medical Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors: Jinming
authors: J
authors: Yang
authors: Sara
authors: S
authors: Kantrow
authors: Jiqing
authors: J
authors: Sai
authors: Oriana E
authors: OE
authors: Hawkins
authors: Mark
authors: M
authors: Boothby
authors: Gregory D
authors: GD
authors: Ayers
authors: Eric D
authors: ED
authors: Young
authors: Elizabeth G
authors: EG
authors: Demicco
authors: Alexander J
authors: AJ
authors: Lazar
authors: Dina
authors: D
authors: Lev
authors: Ann
authors: A
authors: Richmond
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006394:Hemangiosarcoma / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D046888:Tissue Array Analysis; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D016328:NF-kappa B; D051996:Transcription Factor RelA; D051550:I-kappa B Kinase