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.
Highlights
Colorectal cancer (CRC) is the third leading cause of cancer-related death in developed countries [1]
Using a clinically relevant orthotopic implantation murine model, we demonstrate that genistein inhibits human CRC cell metastasis
We demonstrate for the first time that genistein can inhibit the invasion, migration and metastasis of CRC cells
Summary
Colorectal cancer (CRC) is the third leading cause of cancer-related death in developed countries [1]. Increased incidence of CRC has been observed in developing countries, likely due to associated changes in diet and environment. The five-year survival rate exceeds 90% in patients diagnosed with early stage CRC, while it is less than 20% for those with metastatic CRC [2]. The development of metastasis is a major determinant of survival. There are currently no treatments that selectively inhibit processes that drive metastasis. The discovery and development of a safe and effective drug that is able to inhibit human CRC metastasis remains an important goal
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