Intratumoural hypoxia is associated with aggressive and metastatic phenotypes with poor prognosis. The transcription factor HIF-1α is a key regulator of hypoxia-mediated gene expression that is documented to promote tumour growth and metastasis in a wide range of cancers. However its role in the development of thyroid carcinomas is relatively unknown. We have previously shown that HIF-1α is highly active in a range of thyroid cancer cell lines with highest activity observed in the more aggressive cell lines, 8505C and WRO. Furthermore, HIF-1α was not only regulated by hypoxia but by the oncogenic PI3-kinase and MAPK signalling pathways. Analysis of clinical thyroid carcinoma samples showed that the level of HIF-1α and the HIF-1-regulated gene carbonic-anhydrase-9 (CA-9) correlated with increased tumour aggressiveness.
Here we aimed to determine whether this behaviour is important in the development of a metastatic phenotype in vivo.
In vitro cell migration assays revealed that the degree of migration was dependent on the level of oxygen tension and level of thyroid cancer aggressiveness. To determine the degree of metastasis in vivo, BcPAP, FTC133, WRO and 8505C cells were implanted sub-cutaneously on the back of CBA nude mice. Tumour growth rate was analysed and lung and tumour tissue excised. Ex vivo clonogenics of the lungs revealed that all cell lines were highly metastatic, with the most metastatic colonies present from the more aggressive 8505C and WRO-derived tumours. These tumours grew and established faster than FTC133 and BcPAP tumours and had the highest levels of HIF-1α and CA-9 expression.
Our data confirm that HIF-1α plays a key role in thyroid cancer cell migration and metastasis. Blocking HIF-1α by small molecules may be an important therapeutic target in the treatment of thyroid cancer, which will be explored in the metastatic tumour models described above.