Genistein suppresses FLT4 and inhibits human colorectal cancer metastasis
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Xiao Xiao1,*, Zhiguo Liu1,*, Rui Wang1, Jiayin Wang2, Song Zhang1, Xiqiang Cai1, Kaichun Wu1, Raymond C. Bergan3, Li Xu1 and Daiming Fan1
1 State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, Shaanxi Province, PR China
2 The Genome Institute, Washington University in St. Louis, St. Louis, MO, USA
3 Department of Medicine, Robert H. Lurie Cancer Center and Center for Drug Discovery and Chemical Biology of Northwestern University, Chicago, IL, USA
* These authors contributed equally to this work
Li Xu, email:
Daiming Fan, email:
Keywords: colorectal cancer, genistein, FLT4, metastasis, orthotopic mouse model
Received: November 04, 2014 Accepted: December 13, 2014 Published: December 18, 2014
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.
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