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[Cancer Research 62, 4854-4859, September 1, 2002]
© 2002 American Association for Cancer Research

Advances in Brief

Copper Deficiency Induced by Tetrathiomolybdate Suppresses Tumor Growth and Angiogenesis1

Quintin Pan, Celina G. Kleer, Kenneth L. van Golen, Jennifer Irani, Kristen M. Bottema, Carlos Bias, Magda De Carvalho, Enrique A. Mesri, Diane M. Robins, Robert D. Dick, George J. Brewer2 and Sofia D. Merajver2,,3

Department of Internal Medicine, Division of Hematology and Oncology [Q. P., K. L. v. G., J. I., K. M. B., G. J. B., S. D. M.], Departments of Pathology [C. G. K.] and Human Genetics [D. M. R., R. D. D., G. J. B.], and Comprehensive Cancer Center [Q. P., C. G. K., K. L. v. G., K. M. B., S. D. M.], University of Michigan Medical School, Ann Arbor, Michigan 48109, and Laboratory of Viral Oncogenesis, Division of Hematology and Oncology, Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021 [C. B., M. D. C., E. A. M.]

Copper plays an essential role in promoting angiogenesis. Tumors that become angiogenic acquire the ability to enter a phase of rapid growth and exhibit increased metastatic potential, the major cause of morbidity in cancer patients. We report that copper deficiency induced by tetrathiomolybdate (TM) significantly impairs tumor growth and angiogenesis in two animal models of breast cancer: an inflammatory breast cancer xenograft in nude mice and Her2/neu cancer-prone transgenic mice. In vitro, TM decreases the production of five proangiogenic mediators: (a) vascular endothelial growth factor; (b) fibroblast growth factor 2/basic fibroblast growth factor; (c) interleukin (IL)-1{alpha}; (d) IL-6; and (e) IL-8. In addition, TM inhibits vessel network formation and suppresses nuclear factor (NF){kappa}B levels and transcriptional activity. Our study suggests that a major mechanism of the antiangiogenic effect of copper deficiency induced by TM is suppression of NF{kappa}B, contributing to a global inhibition of NF{kappa}B-mediated transcription of proangiogenic factors.




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