Copper deficiency induced by tetrathiomolybdate suppresses tumor growth and angiogenesis.
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)-1alpha; (d) IL-6; and (e) IL-8. In addition, TM inhibits vessel network formation and suppresses nuclear factor (NF)kappaB levels and transcriptional activity. Our study suggests that a major mechanism of the antiangiogenic effect of copper deficiency induced by TM is suppression of NFkappaB, contributing to a global inhibition of NFkappaB-mediated transcription of proangiogenic factors.
Pan
Quintin
Q
Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Kleer
Celina G
CG
van Golen
Kenneth L
KL
Irani
Jennifer
J
Bottema
Kristen M
KM
Bias
Carlos
C
De Carvalho
Magda
M
Mesri
Enrique A
EA
Robins
Diane M
DM
Dick
Robert D
RD
Brewer
George J
GJ
Merajver
Sofia D
SD
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D003300:Copper / Q000172:deficiency*; D004195:Disease Models, Animal; D005260:Female; D018734:Genes, erbB-2; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D008982:Molybdenum / Q000494:pharmacology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D016328:NF-kappa B; D003300:Copper; D008982:Molybdenum; C020809:tetrathiomolybdate