The Effect of Tetrathiomolybdate on Cytokine Expression, Angiogenesis, and Tumor Growth in Squamous Cell Carcinoma of the Head and Neck

Department of Otolaryngology-Head and Neck Surgery, University of Michigan Medical Center, Ann Arbor, MI 48103, USA.
Archives of Otolaryngology - Head and Neck Surgery (Impact Factor: 2.33). 04/2005; 131(3):204-11. DOI: 10.1001/archotol.131.3.204
Source: PubMed


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

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    • "Copper has since shown to be a direct stimulator of endothelial cell proliferation and migration [27,28]. Additionally, copper is a required cofactor for the activity, production and secretion of key angiogenic cytokines up-regulated in head and neck cancers [5,29]. Tetrathiomolybdate (TM) is a potent chelator of copper that has been widely studied for its good oral bioavailability, low toxicity profile and its tumor suppressive effects [25,30,31]. "
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    ABSTRACT: The metastatic spread of solid tumors is directly or indirectly responsible for most cancer-related deaths. Tumor metastasis is very complex and this process requires a tumor cell to acquire enhanced motility, invasiveness and anoikis resistance to successfully establish a tumor at a distal site. Metastatic potential of tumor cells is directly correlated with the expression levels of several angiogenic cytokines. Copper is a mandatory cofactor for the function of many of these angiogenic mediators as well as other proteins that play an important role in tumor cell motility and invasiveness. We have previously shown that tetrathiomolybdate (TM) is a potent chelator of copper and it mediates its anti-tumor effects by suppressing tumor angiogenesis. However, very little is known about the effect of TM on tumor cell function and tumor metastasis. In this study, we explored the mechanisms underlying TM-mediated inhibition of tumor metastasis. We used two in vivo models to examine the effects of TM on tumor metastasis. Animals treated with TM showed a significant decrease in lung metastasis in both in vivo models as compared to the control group. In addition, tumor cells from the lungs of TM treated animals developed significantly smaller colonies and these colonies had significantly fewer tumor cells. TM treatment significantly decreased tumor cell motility and invasiveness by inhibiting lysyl oxidase (LOX) activity, FAK activation and MMP2 levels. Furthermore, TM treatment significantly enhanced tumor cell anoikis by activating p38 MAPK cell death pathway and by downregulating XIAP survival protein expression. Taken together, these results suggest that TM is a potent suppressor of head and neck tumor metastasis by modulating key regulators of tumor cell motility, invasiveness and anoikis resistance.
    Full-text · Article · Aug 2010 · Molecular Cancer
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    • "The mechanism by which ATM exerts its anti-angiogenic and anti-cancer effect has been investigated in several research studies. ATM has been shown to decrease the secretion of several cytokines, that are crucial for the progression and survival of cancer cells, including VEGF-A,B, bFGF, IL- 6 TNF-a [6] [7] [8]. Additionally, NF K B signaling is one of the important pathways in maintaining the proliferation and survival of cancer cells. "
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    ABSTRACT: This study examines the target specificity of tetrathiomolybdate (ATM), an anti-angiogenic, anti-tumor agent against the viability / proliferation of arterial, venous, capillary endothelial and tumor cells. Cells were seeded at 10 or 100% density (to measure viability / proliferation respectively) in medium +/- 0-250 uM ATM. Viability and proliferation were measured by metabolic labeling-colorimetry. One-way ANOVA + Bonferroni testing examined base metabolism; Dunnett's testing was used for viability/proliferation. Venous proliferation showed high ATM sensitivity (50% reduction ~ > or =5 uM ATM, p<0.01), capillary proliferation was inhibited > or =10 uM (p<0.05). Arterial endothelium were less sensitive to ATM, (50% inhibition ~ > or = 20 uM, p<0.01). YPEN-1 were inhibited >50 uM ATM. Capillary viability was inhibited > or =20 microM ATM (p<0.01); venous, arterial and tumor viability show less ATM sensitivity. Our data suggest that venous and capillary endothelial proliferation are important targets in ATM therapy, but that other vascular segments and tumor cells may be less influenced.
    Preview · Article · Jan 2008 · Inflammation Research
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    ABSTRACT: Copper stimulates the proliferation and migration of endothelial cells and is required for the secretion of several angiogenic factors by tumour cells. Copper chelation decreases the secretion of many of these factors. Serum copper levels are upregulated in many human tumours and correlate with tumour burden and prognosis. Copper chelators reduce tumour growth and microvascular density in animal models. New orally active copper chelators have enabled clinical trials to be undertaken, and there are several studies ongoing. A unifying mechanism of action by which copper chelation inhibits endothelial cell proliferation and tumour secretion of angiogenic factors remains to be elucidated, but possible targets include copper-dependent enzymes, chaperones, and transporters.
    No preview · Article · Nov 2005 · Journal of Mammary Gland Biology and Neoplasia
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