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


METHODS
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.


METHODS
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.
Teknos
Theodoros N
TN
Department of Otolaryngology-Head and Neck Surgery, University of Michigan Medical Center, Ann Arbor, MI 48103, USA. teknos@umich.edu
Islam
Mozaffarul
M
Arenberg
Douglas A
DA
Pan
Quintin
Q
Carskadon
Shannon L
SL
Abarbanell
Aaron M
AM
Marcus
Benjamin
B
Paul
Supriti
S
Vandenberg
Curtis D
CD
Carron
Michael
M
Nor
Jacques E
JE
Merajver
Sofia D
SD
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D001707:Biopsy, Needle; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D051379:Mice; D016513:Mice, SCID; D008982:Molybdenum / Q000494:pharmacology*; D009389:Neovascularization, Pathologic; D011336:Probability; D051381:Rats; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D013045:Species Specificity; D047368:Tumor Burden / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D016207:Cytokines; D008982:Molybdenum; C020809:tetrathiomolybdate