The effect of tetrathiomolybdate on cytokine expression, angiogenesis, and tumor growth in squamous cell carcinoma of the head and neck.

Abstract

OBJECTIVE:

To assess the effect of tetrathiomolybdate on cytokine expression, angiogenesis, and tumor growth rate in human squamous cell carcinoma (SCC).

DESIGN:

Three human SCC cell lines were used in this study for both in vitro and in vivo investigations. Conditioned media from untreated and tetrathiomolybdate-treated cell lines were compared with regard to cytokine levels, endothelial cell chemotaxis, endothelial cell tubule formation, and migration and the ability to induce angiogenesis in a rat aortic ring array. In vivo UM-SCC-38 was seeded onto tissue-engineered scaffolds and surgically implanted into the flanks of immunodeficient mice. Tumor growth rates and the level of angiogenesis were compared after 2 weeks of therapy.

SETTING:

A tertiary care facility.

RESULTS:

In this study, we demonstrate that tetrathiomolybdate significantly decreases the secretion of interleukin 6 and basic fibroblast growth factor by head and neck SCC (HNSCC) cell lines in vitro. Furthermore, we demonstrate that tetrathiomolybdate significantly decreases the secretion of interleukin 6 and basic fibroblast growth factor by HNSCC cell lines in vitro. Furthermore, tetrathiomolybdate treatment of HNSCC cell lines results in significantly decreased endothelial cell chemotaxis, tubule formation, and neovascularization in a rat aortic ring assay. This in vitro evidence of decreased angiogenesis by tetrathiomolybdate is confirmed in vivo by using a severe combined immunodeficiency disorder mouse model in which tetrathiomolybdate therapy is shown to prevent human blood vessel formation. Finally, human HNSCC implanted into immunodeficient mice grow to a much larger size in untreated mice compared with those treated with 0.7 mL/kg per day of oral tetrathiomolybdate.

CONCLUSIONS:

These findings illustrate the ability of tetrathiomolybdate to down-regulate proinflammatory and proangiogenic cytokines in HNSCC. These observations are potentially exciting from a clinical perspective because a global decrease in these cytokines may decrease tumor aggressiveness and reverse the resistance to chemotherapy and radiation therapy seen in this tumor type.

• Authors: Theodoros N Teknos, Mozaffarul Islam, Douglas A Arenberg, Quintin Pan, Shannon L Carskadon, Aaron M Abarbanell, Benjamin Marcus, Supriti Paul, Curtis D Vandenberg, Michael Carron, Jacques E Nor, Sofia D Merajver
• Journal: Archives of otolaryngology--head & neck surgery (Arch Otolaryngol Head Neck Surg) Vol. 131 Issue 3 Pg. 204-11 (Mar 2005) ISSN: 0886-4470 [Print] United States
• PMID: 15781759 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Angiogenesis Inhibitors
• Biomarkers, Tumor
• Cytokines
• Molybdenum
• tetrathiomolybdate

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Biomarkers, Tumor (analysis)
• Biopsy, Needle
• Carcinoma, Squamous Cell (pathology)
• Cell Movement (drug effects)
• Cytokines (drug effects, metabolism)
• Disease Models, Animal
• Endothelial Cells (cytology, drug effects)
• Enzyme-Linked Immunosorbent Assay
• Head and Neck Neoplasms (pathology)
• Humans
• Immunohistochemistry
• In Vitro Techniques
• Mice
• Mice, SCID
• Molybdenum (pharmacology)
• Neovascularization, Pathologic
• Probability
• Rats
• Rats, Sprague-Dawley
• Risk Assessment
• Sensitivity and Specificity
• Species Specificity
• Tumor Burden (drug effects)
• Tumor Cells, Cultured