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


RESULTS
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.


CONCLUSIONS
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.
Kumar
Pawan
P
Department of Otolaryngology-Head and Neck Surgery and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA. pawan.kumar@osumc.edu
Yadav
Arti
A
Patel
Samip N
SN
Islam
Mozaffarul
M
Pan
Quintin
Q
Merajver
Sofia D
SD
Teknos
Theodoros N
TN
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D023102:Anoikis; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D002478:Cells, Cultured; D006258:Head and Neck Neoplasms / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D008982:Molybdenum / Q000494:pharmacology*; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D009362:Neoplasm Metastasis / Q000517:prevention & control*
D020533:Angiogenesis Inhibitors; D008982:Molybdenum; C020809:tetrathiomolybdate