Fumagillin inhibits colorectal cancer growth and metastasis in mice: in vivo and in vitro study of anti-angiogenesis.
Fumagillin is an inhibitor of type 2 methionine aminopeptidase that can block blood vessel formation, but its molecular mechanism and therapeutic value in colon cancer still remain to be elucidated. In this study, male severe combined immunodeficiency (SCID) mice were injected with colon cancer cells in the subcutis and then treated with Fumagillin and Cyclo (Arg-Gly-Asp-D-Phe-Val), an integrin alphavbeta(3) antagonist. The tumor weight, microvessel density (MVD), and number of pulmonary metastatic foci were examined. Gene expression profiles were examined by microarray analysis of human umbilical endothelial cells (HUVEC). The Fumagillin-treated mice had smaller tumor mass, fewer pulmonary metastases, and lower MVD-CD105 levels than control animals. In vitro proliferation and tube formation of HUVEC was also significantly decreased by Fumagillin. Microarray analysis of Fumagillin-treated HUVEC showed upregulation of 71 genes and downregulation of 143 genes. Expression changes were involved in cell proliferation, migration, adhesion, and gene transcription. Quantitative real-time-polymerase chain reaction and western blotting showed decreased expression of cyclin E2, activated leukocyte cell adhesion molecule (ALCAM), and intercellular adhesion molecule-1 (ICAM-1) genes in the presence of Fumagillin. This downregulation by Fumagillin may be involved in the anti-angiogenesis by Fumagillin. In conclusion, Fumagillin was found to suppress colorectal cancer growth and metastasis by suppressing angiogenesis.
Hou
Li
L
Department of Pathology and Biodefense, Faculty of Medicine, Saga University, Saga, Japan.
Mori
Daisuke
D
Takase
Yukari
Y
Meihua
Piao
P
Kai
Keita
K
Tokunaga
Osamu
O
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000188:drug therapy*; D003510:Cyclohexanes / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D005312:Fetal Blood; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012717:Sesquiterpenes / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D012717:Sesquiterpenes; C026211:fumagillin