Tetrathiomolybdate inhibits head and neck cancer metastasis by decreasing tumor cell motility, invasiveness and by promoting tumor cell anoikis

Pawan Kumar,Mozaffarul Islam,Arti Yadav,Theodoros N Teknos,Quintin Pan,Samip N Patel,Sofia D Merajver

doi:10.1186/1476-4598-9-206

Pawan Kumar, Mozaffarul Islam + Show 5 more

Open Access

https://doi.org/10.1186/1476-4598-9-206

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Abstract

BackgroundThe 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.ResultsWe 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.ConclusionsTaken 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.

Highlights

The metastatic spread of solid tumors is directly or indirectly responsible for most cancer-related deaths
TM treatment significantly inhibited EC-Bcl-2 mediated tumor growth and angiogenesis We have previously shown that elevated expression of Bcl-2 in tumor-associated endothelial cells directly correlates with tumor metastasis in head and neck cancer patients [14]
We demonstrated that coimplantation of EC-Bcl-2 along with oral squamous carcinoma cells (OSCC-3) in Severe combined immunodeficiency disease (SCID) mice significantly enhances tumor growth and tumor metastasis to lungs

Summary

Introduction

The metastatic spread of solid tumors is directly or indirectly responsible for most cancer-related deaths. Metastatic potential of tumor cells is directly correlated with the expression levels of several angiogenic cytokines. The high mortality associated with advanced head and neck cancers is in large part due to the local spread by primary tumors as well as distal tumor metastasis to vital organs [3,4]. HNSCC tumors and their vasculature express numerous angiogenic cytokines including vascular endothelial growth factor (VEGF), interleukin (IL) 1a, IL-6, IL-8, and fibroblast growth factor (FGF) [5,6,7] which facilitate tumor growth and progression. Tumor samples from head and neck cancer patients showed significantly higher Bcl-2 expression in tumor blood vessels [13] and this enhanced Bcl-2 expression in tumor-associated endothelial cells was directly correlated with metastatic status of these patients [14]. Upregulated Bcl-2 expression in tumor-associated endothelial cells was sufficient to enhance tumor angiogenesis, tumor progression and tumor metastasis of oral squamous cell carcinoma in a SCID mouse model [14]

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