Iodine-deficiency-induced long lasting angiogenic reaction in thyroid cancers occurs via a vascular endothelial growth factor-hypoxia inducible factor-1-dependent, but not a reactive oxygen species-dependent, pathway.
BACKGROUND
In the thyroid, iodine deficiency (ID) induces angiogenesis via a tightly controlled reactive oxygen species (ROS)-hypoxia inducible factor-1 (HIF-1)-vascular endothelial growth factor (VEGF) dependent pathway (ROS-HIF-VEGF). Deficient iodine intake may be associated with increased thyroid cancer incidence. The hypothesis of this work is to test whether ID affects the angiogenic processes in thyroid malignant cells by altering the ROS-HIF-VEGF pathway.


METHODS
Goiters were obtained in RET/PTC3 transgenic and wild-type (wt) mice and ID was induced in three thyroid carcinoma cell lines (TPC-1, 8305c, and R082-w1). Thyroid blood flow, VEGF mRNA and protein, and HIF-1α protein expression were measured. The role of HIF-1 and of ROS was assessed using echinomycin and N-acetylcysteine (NAC), respectively.


RESULTS
The goitrogen treatment increased the thyroid blood flow in wt and RET/PTC3 mice. Compared with wt mice, basal VEGF expression was higher in RET/PTC3 mice and increased with goitrogen treatment. In the three cell lines, ID induced marked increases in VEGF mRNA, and moderate increases in HIF-1α protein expression that were not transient as in normal cells. ID-induced VEGF mRNA expression was fully (8305c), partially (TPC-1), or not (R082-w1) blocked by echinomycin. NAC had no effect on ID-induced VEGF mRNA and HIF-1α protein expression in the three cell lines.


CONCLUSIONS
ID induces a long lasting angiogenic phenotype in thyroid cancer cells that occurs through VEGF induction via a pathway partially mediated by HIF-1, but not by ROS. These results suggest that, in contrast with normal cells, ID-induced angiogenesis in cancer cells occurs via alternative and likely less controlled routes, thereby leading to uncontrolled growth.
Department of Morphology, Institute of Experimental and Clinical Research, Catholic University of Louvain, Brussels, Belgium. anne-catherine.gerard@uclouvain.be
Anne-Catherine
AC
Gérard
Kevin
K
Humblet
Cindy
C
Wilvers
Sylvie
S
Poncin
Hanane
H
Derradji
Christine
C
de Ville de Goyet
Khalil
K
Abou-el-Ardat
Sarah
S
Baatout
Pierre
P
Sonveaux
Jean-François
JF
Denef
Ides M
IM
Colin
D000818:Animals; D002277:Carcinoma / Q000098:blood supply / Q000378:metabolism*; D045744:Cell Line, Tumor; D003677:Deficiency Diseases / Q000150:complications / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007455:Iodine / Q000172:deficiency*; D017078:Laser-Doppler Flowmetry; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D017382:Reactive Oxygen Species / Q000378:metabolism; D027981:Symporters / Q000378:metabolism; D013961:Thyroid Gland / Q000098:blood supply / Q000000981:diagnostic imaging; D013964:Thyroid Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging / Q000378:metabolism*; D014463:Ultrasonography; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D000099209:Sodium-Iodide Symporters
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007455:Iodine; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D027981:Symporters; D042461:Vascular Endothelial Growth Factor A; D000099209:Sodium-Iodide Symporters; C497443:Hif1a protein, mouse; C467480:vascular endothelial growth factor A, mouse