Nuclear factor κB-dependent regulation of angiogenesis, and metastasis in an in vivo model of thyroid cancer is associated with secreted interleukin-8.
BACKGROUND
Development of novel strategies in the treatment of advanced thyroid cancer are needed. Our laboratory has previously identified a role for nuclear factor κB (NF-κB) signaling in human thyroid cancer cell growth, survival, and invasion.


OBJECTIVE
Our goal was to establish the role of NF-κB signaling on thyroid cancer growth and metastases in vivo and to begin to dissect mechanisms regulating this effect.


METHODS
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-κB signaling by overexpression of a dominant-negative IκBα (mIκBα) significantly inhibited thyroid tumor growth in tumors derived from both cell lines. Further studies in an experimental metastasis model demonstrated that NF-κB 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 mIkBα only in the BCPAP cells. Cytokine antibody array analysis demonstrated that IL-8 secretion was blocked by mIκBα expression. Interestingly, basal NF-κB 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-κB and IL-8 are associated with more aggressive tumor behavior.


CONCLUSIONS
These studies suggest that NF-κB 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-κB signaling in advanced thyroid cancer growth and progression.
Departments of Medicine and Pathology, Division of Endocrinology, Metabolism, and Diabetes (K.T.B., R.E.S., G.L., N.P., W.M.W., B.R.H.), University of Colorado School of Medicine, Aurora, Colorado 80045; University of Colorado Cancer Center (R.E.S., G.D., R.A., W.M.W., B.R.H.), University of Colorado School of Medicine, Aurora, Colorado 80045; CCF Pathology and Laboratory Medicine Institute (G.K.), Cleveland, Ohio 44120; and Skaggs School of Pharmacy and Pharmaceutical Sciences (G.K., R.A.), University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado 80045.
Kevin T
KT
Bauerle
Rebecca E
RE
Schweppe
Gregory
G
Lund
Gregory
G
Kotnis
Gagan
G
Deep
Rajesh
R
Agarwal
Nikita
N
Pozdeyev
William M
WM
Wood
Bryan R
BR
Haugen
D000818:Animals; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics; D016209:Interleukin-8 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000473:pathology*
C508606:CXCL8 protein, human; D020672:I-kappa B Proteins; D016209:Interleukin-8; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha