Anti-metastatic potential of anthocyanins and their metabolites (metabotypes) on cancer cell lines with different phenotypes - role of intestinal fermentation and metabolization.

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With about 20-30%, cancer is the second leading cause of death in Germany. The aggressiveness of a tumor depends on its metastasizing potential, which is characterized by the steps of invasion, intravasation and extravasation. New pharmacological therapeutics particularly aim at inhibiting cell adhesion molecules of tumor cells, e.g. integrins, selectins, and members of the immunoglobulin superfamily whose expression and pattern is strongly associated with the metastatic potential. They aim at the inhibition of tumor cell extravasation into the tissues and the formation of metastases. Nutritive factors that are able to influence these processes are currently being intensively investigated. Primarily, anthocyanins (ACN) belonging to the secondary plant ingredients are of particular importance. Their bioavailability is low, and they reach the lower gastrointestinal tract largely unchanged. Here, microbial fermentation products may be generated which could induce anti-carcinogenic effects after being absorbed into the systemic circulation. Preliminary experiments showed that ACN fermented by bacteria typically present in the human intestinal microbiota such as E. coli and Haf. alvei significantly reduced the migration of colorectal carcinoma and pancreatic carcinoma cells in vitro. Similarly, after the intake of an ACN-rich juice, ACN and their metabolites isolated from human plasma (PiACN) were able to influence tumor cell migration, but not to affect growth-associated parameters. This anti-migrative effect was not only dependent on the time of blood collection (60 min or 14 days after juice intake), but also on the individual subject. It is completely unclear which compounds are responsible for these effects and by which mechanism they induce these effects. The aim of the proposal is to investigate which ACNs and metabolites were generated after a 4-week-intervention study with an ACN-rich juice and if they are able to induce an anti-cancerogenic effect. The PiACN derived from all subjects before and after the intervention phase will be prepared by solid phase extraction and used for the in vitro functional studies. Pancreatic (Panc-1, Asp-1) and colon (HT-29, Caco-2) cancer cell lines as well as endothelial cells (HUVEC) will be investigated regarding their expression levels of β integrins, selectins and members of the immunoglobulin superfamily. The involvement of relevant signaling pathways (FAK-SFK- and redox-sensitive NF-B-associated signaling pathway) are also of interest. Besides the effects of PiACN on these cells itself, its effect regarding with pharmacologically relevant compounds is to be investigated in vitro in order to identify possible interactions. The analysis of blood and fecal samples with regard to ACN and their metabolites, as well as the composition of the intestinal microbiota, should provide further information on the interactions between function and metabolism.