Tetrathiomolybdate promotes tumor necrosis and prevents distant metastases by suppressing angiogenesis in head and neck cancer

Angiogenesis is well recognized as an essential process that influences not only the growth of head and neck squamous cell carcinoma (HNSCC) but also promotes its invasive and metastatic behavior. The critical role of copper in multiple facets of angiogenesis makes it an important therapeutic target. Tetrathiomolybdate is a potent copper chelator, which has shown remarkable ability to suppress angiogenesis. Although this may involve multiple mechanisms, the effects on vascular endothelial growth factor (VEGF) are pivotal. In previous work, tetrathiomolybdate suppressed production of several proangiogenic cytokines by HNSCC cell lines. Given these results, we hypothesized that tetrathiomolybdate would impair tumor growth and metastasis by HNSCC. To test this concept, we evaluated the effects of long-term tetrathiomolybdate treatment on the growth and metastatic progression of HNSCC using a xenograft animal model. The results showed that tetrathiomolybdate treatment is able to maintain effective inhibition of angiogenesis. There was a significant reduction in the tumor size and vascularity with evident gross necrosis in the tetrathiomolybdate-treated animals. These effects were highly correlated with suppression of human VEGF expressed in the developing tumors as well as the mouse VEGF levels detected in the plasma. Moreover, tetrathiomolybdate treatment drastically suppressed the development of lung metastases. Taken together, these results show that tetrathiomolybdate can act long-term as a suppressor of vascularity and inhibit the growth of metastasis in this model of HNSCC.