title: Genistein suppresses FLT4 and inhibits human colorectal cancer metastasis.
abstract: Dietary consumption of genistein, found in soy, has been associated with a potentially protective role in colorectal cancer (CRC) development and progression. Herein we demonstrate that genistein will inhibit human CRC cell invasion and migration, that it does so at non-cytotoxic concentrations and we demonstrate this in multiple human CRC cell lines. After orthotopic implantation of human CRC tumors into mice, oral genistein did not inhibit tumor growth, but did inhibit distant metastasis formation, and was non-toxic to mice. Using a qPCR array, we screened for genistein-induced changes in gene expression, followed by Western blot confirmation, demonstrating that genistein downregulated matrix metalloproteinase 2 and Fms-Related Tyrosine Kinase 4 (FLT4; vascular endothelial growth factor receptor 3). After demonstrating that genistein suppressed neo-angiogenesis in mouse tumors, we examined FLT4 expression in primary CRC and adjacent normal colonic tissue from 60 human subjects, demonstrating that increased FLT4 significantly correlates with increased stage and decreased survival. In summary, we demonstrate for the first time that genistein inhibits human CRC metastasis at dietary, non-toxic, doses. FLT4 is identified as a marker of metastatic disease, and as a response marker for small molecule therapeutics that inhibit CRC metastasis.
authors.affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, PR China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiao
authors.affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, PR China.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, PR China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: The Genome Institute, Washington University in St. Louis, St. Louis, MO, USA.
authors.forename: Jiayin
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, PR China.
authors.forename: Song
authors.initials: S
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, PR China.
authors.forename: Xiqiang
authors.initials: X
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, PR China.
authors.forename: Kaichun
authors.initials: K
authors.lastname: Wu
authors.affiliation: Department of Medicine, Robert H. Lurie Cancer Center and Center for Drug Discovery and Chemical Biology of Northwestern University, Chicago, IL, USA.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Bergan
authors.affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, PR China.
authors.forename: Daiming
authors.initials: D
authors.lastname: Fan
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019833:Genistein / Q000494:pharmacology*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic; D013997:Time Factors; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D019833:Genistein; C581309:FLT4 protein, human; D040321:Vascular Endothelial Growth Factor Receptor-3