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.

Risks and benefits related to alimentary exposure to xenoestrogens

“…These effects were completely antagonized by ERs antagonist fulvestrant (Schleipen et al, 2011). In mice implanted with human colorectal cancer tumors, orally administered genistein did not inhibit tumor growth, but it did inhibit distant metastasis formation, and displayed no toxicity (Xiao et al, 2014). Apigenin and naringenin showed to be effective in the reduction of ER-mediated cell growth in non-malignant young adult mouse colonocytes (YAMC) and, interestingly, when administered in combination, they showed a strong enhanced activity with significantly lower concentration compared to the single administration (Yang et al, 2014).…”

Genistein decreases A549 cell viability via inhibition of the PI3K/AKT/HIF-1α/VEGF and NF-κB/COX-2 signaling pathways

“…Genistein, a natural phytoestrogen found in soy, has demonstrated the potential to inhibit numerous types of cancer, including breast, pancreatic and colorectal cancers (13)(14)(15). Previous studies have indicated that this effect may be due to its ability to induce cancer cell apoptosis, arrest the cell cycle and inactivate critical signaling pathways in human cancer cells (16,17).…”

Dietary Intervention by Phytochemicals and Their Role in Modulating Coding and Non-Coding Genes in Cancer

“…The validation on orthotopic mice models, of colorectal tumours, the genistein treatment (oral delivery) did not significantly reduced tumour growth, but was able to prevent distant metastasis [110]. In oral cancer the antimetastatic effect was related by regulating the MMP-2 expression by inhibition of ERK1/2 and the activator protein-1 signalling pathways [111].…”