INK4a/ARF [corrected] inactivation with activation of the NF-?B/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-?B 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-?B 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 Ikk? solely in myeloid cells was insufficient to block angiosarcoma development; in contrast, systemic inhibition of Ikk?, 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.

SUBMITTER: Yang J 

PROVIDER: S-EPMC3459578 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature