INK4a/ARF [corrected] inactivation with activation of the NF-κB/IL-6 pathway is sufficient to drive the development and growth of angiosarcoma.

Yang J, Kantrow S, Sai J, Hawkins OE, Boothby M, Ayers GD, Young ED, Demicco EG, Lazar AJ, Lev D, Richmond A
Cancer Res. 2012 72 (18): 4682-95

PMID: 22836752 · PMCID: PMC3459578 · DOI:10.1158/0008-5472.CAN-12-0440

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.

MeSH Terms (16)

Animals Blotting, Western Disease Models, Animal Enzyme-Linked Immunosorbent Assay Flow Cytometry Hemangiosarcoma Humans I-kappa B Kinase Interleukin-6 Mice Mice, Knockout NF-kappa B Real-Time Polymerase Chain Reaction Signal Transduction Tissue Array Analysis Transcription Factor RelA

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