Nuclear Factor κB-Dependent Regulation of Angiogenesis, and Metastasis in an In Vivo Model of Thyroid Cancer Is Associated With Secreted Interleukin-8

Context: Development of novel strategies in the treatment of advanced thyroid cancer are needed. Our laboratory has previously identified a role for nuclear factor kappa B (NF-kappa B) signaling in human thyroid cancer cell growth, survival, and invasion. Objective: Our goal was to establish the role of NF-kappa B signaling on thyroid cancer growth and metastases in vivo and to begin to dissect mechanisms regulating this effect. Setting and Design: We examined tumor formation of five thyroid cancer cell lines in an in vivo model of thyroid cancer and observed tumor establishment in two of the cell lines (8505C and BCPAP). Results: Inhibition of NF-kappa B signaling by overexpression of a dominant-negative I kappa B alpha (mI kappa B alpha) significantly inhibited thyroid tumor growth in tumors derived from both cell lines. Further studies in an experimental metastasis model demonstrated that NF-kappa B inhibition impaired growth of tumor metastasis and prolonged mouse survival. Proliferation (mitotic index) was decreased in 8505C tumors, but not in BCPAP tumors, while in vitro angiogenesis and in vivo tumor vascularity were significantly inhibited by mIkB alpha only in the BCPAP cells. Cytokine antibody array analysis demonstrated that IL-8 secretion was blocked by mI kappa B alpha expression. Interestingly, basal NF-kappa B activity and IL-8 levels were significantly higher in the two tumorigenic cell lines compared with the nontumorigenic lines. Furthermore, IL-8 transcript levels were elevated in high-risk human tumors, suggesting that NF-kappa B and IL-8 are associated with more aggressive tumor behavior. Conclusions: These studies suggest that NF-kappa B signaling is a key regulator of angiogenesis and growth of primary and metastatic thyroid cancer, and that IL-8 may be an important downstream mediator of NF-kappa B signaling in advanced thyroid cancer growth and progression.