Ikk4a/Arf Inactivation with Activation of the NF-κB/IL-6 Pathway Is Sufficient to Drive the Development and Growth of Angiosarcoma
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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. Cancer Res; 72(18); 4682–95. ©2012 AACR.
Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
- Received February 6, 2012.
- Revision received July 12, 2012.
- Accepted July 17, 2012.
- ©2012 American Association for Cancer Research.