Isoflavone Research Initiative

A highly complex cascade of receptors, enzymes and mediators is involved in the signalling chain of angiogenesis. In animal experiments soy preparations inhibit cancer development, which is expressed by a reduced formation of microcapillaries in the tumour (Guo et al. 2007).

The vascular endothelial growth factor (VEGF) is an important mediator for the creation of new blood vessels (angiogenesis). VEGF is involved in the communication between tumour tissue and vascular endothelium. It translates the increased need of the tumour for blood supply into the new formation of capillaries. The tumour itself takes care of an increased expression of VEGF. Consequently, a high expression of VEGF correlates with a poor prognosis of cancer development (Anandanadesan et al. 2007).
 
The formation of VEGF in tumour tissue is the result of a complex activation. In invasive cancer of the pancreas a relation between increased formation of VEGF and a high expression of the angiotensin-II-receptor type 1 was found. This receptor induces the formation of VEGF in pancreatic cancer cells, making the angiotensin-II-receptor type 1 a potential therapeutic target for cancer treatment: the suppression of effects mediated by this receptor correlates with a lower formation of VEGF. A lower formation of VEGF translates into reduced neoangiogenesis, and by consequence a deterioration of the supply of the tumour with oxygen and nutrients (Anandanadesan et al. 2007).

Basically, there are various approaches of interfering with the cascade “angiotensin-II-receptor type 1 – formation of VEGF – formation of new blood vessels for the supply of the tumour” on the level of the receptor: One approach is to directly block the receptor, which would, however, lead to undesired effects, as this receptor has also other important functions in the human organism. Genistein has no direct effects at the angiotensin receptor itself. The alternative approach – taken by genistein – is to inhibit the signal transduction of the receptor towards the expression of VEGF. This signal transduction from the receptor to the gene involves the activation of mediators by phosphorylation. Among the phosphorylating kinases one key enzyme is the extracellular signal-regulated kinase ERK1/2: Inhibition of this specific kinase means that the signal of the angiotensin receptor will be attenuated and not lead to the full activation of VEGF (Anandanadesan et al. 2007). It is therefore not necessary to inhibit the angiotensin receptor itself. An inhibition of its signal transduction – as achievable through genistein – will have the same outcome.

Another significant pathway of induction of the formation of VEGF is the reaction of tumour cells to hypoxia. Oxygen deficiency in the tumour tissue enhances VEGF expression, and thus leads to an increased formation of microcapillaries. The signal is transmitted through the formation of factor 1α, a transcription factor for VEGF.
As could be shown in vitro in umbilical cord endothelial cells, genistein inhibits the signal transduction for neoangiogenesis via VEGF through various pathways:

• Genistein inhibits the formation of factor 1α, and thus blocks one of the transcription factors of VEGF – which finally results in an inhibition of angiogenesis. Genistein thus disrupts the communication between tumour cells and vascular endothelial cells (Guo et al. 2007).
• This latter mechanism inhibits the de novo formation of VEGF. Genistein has, however, also effects on neoangiogenesis when VEGF is already present. Incubation of human endothelial cells with VEGF triggers self-organisation of the endothelial cells towards the formation of microcapillaries. The same effect can be observed when the endothelial cells are incubated with cultivation medium of human prostate cancer cells – a medium which contains VEGF formed by the cancer cells. Under such conditions co-incubation with genistein inhibits the growth of endothelial cells with a half-maximal concentration of ≤20 μM. This means that there is more than one mechanism of action involved in the inhibition of VEGF-effects by genistein: the isoflavone does not only inhibit the new formation of VEGF, but also inhibits the pro-angiogenetic effects of already present VEGF (Guo et al. 2007).

In an analysis of gene activity of human umbilical cord endothelial cells, genistein at a concentration of 10 µM had inhibiting and promoting effects on the expression of 256 genes, among them genes involved in cell proliferation, transcription, translation, apoptosis and kinases. Genes related to cell adhesion were down-regulated, which was expressed in a decreased adhesion of the endothelial cells – again an effect directed against angiogenesis (Piao et al. 2006). This latter effect may explain why genistein can still inhibit angiogenesis when the endothelial growth factor is already present.

Inhibition of the formation of VEGF by genistein has been confirmed in human breast cancer and glioma cells. Similar effects in vitro were also observed for structurally similar compounds such as flavonoids (naringenin, rutin, apigenin, kaempferol, chrysin) (Schindler and Mentlein 2006).

In conclusion, the inhibition of VEGF effects is most likely one of the major mechanisms of cancer preventive effects observed in epidemiological and clinical examinations of isoflavones.

References

Anandanadesan, R., Gong, Q., Chipitsyna, G., Witkiewicz, A., Yeo, C. J., and Arafat, H. A. (2007). Angiotensin II Induces Vascular Endothelial Growth Factor in Pancreatic Cancer Cells Through an Angiotensin II Type 1 Receptor and ERK1/2 Signaling. J. Gastrointest. Surg. 12: 57-66.

Guo, Y., Wang, S., Hoot, D. R., and Clinton, S. K. (2007). Suppression of VEGF-mediated autocrine and paracrine interactions between prostate cancer cells and vascular endothelial cells by soy isoflavones. J. Nutr. Biochem. 18 (6): 408-417.

Piao, M., Mori, D., Satoh, T., Sugita, Y., and Tokunaga, O. (2006). Inhibition of endothelial cell proliferation, in vitro angiogenesis, and the down-regulation of cell adhesion-related genes by genistein. Combined with a cDNA microarray analysis. Endothelium 13 (4): 249-266.

Schindler, R. and Mentlein, R. (2006). Flavonoids and vitamin E reduce the release of the angiogenic peptide vascular endothelial growth factor from human tumor cells. J. Nutr. 136 (6): 1477-1482.