Tumor progression: new targets and nutraceutical approaches

Cancer development is a complicated and multistep process that drives the progressive transformation of normal human cells into highly malignant derivatives through genetic alterations. Successive mutations in oncogenes and tumor-suppressor genes virtually result in enhanced proliferation and resistance to cell death. These genes play a central role in the genesis and progression of human cancers, as their frequent alterations have been found in a variety of human cancers. Furthermore, inflammation is a key component of the tumor microenvironment that acts as a key regulator of tumor promotion and progression by several mechanisms. Due to the complexity of the numerous pathways involved in cancer progression and the increasingly frequent onset of the phenomenon of resistance to anticancer drugs in some tumors, current research focuses on discover of new targets and new approaches for cancer treatment. In this work, we analysed two key objectives of cancer research: anticancer activity of natural compounds and identification of new possible molecular targets for therapy and diagnosis. In the first part of the work we studied the effects of two different natural compounds/extracts on cellular pathways altered in cancer. In particular, we evaluated the activity of oat-derivatives, the Avenanthramides, on cell proliferation, migration and EMT, focusing on EGFR signalling pathway, and the antioxidant, antinflammatory and antiproliferative effects of an extract of a rare variety of common bean (Phaseolus Vulgaris L. Var Venanzio) growth in South of Tuscany. In the second part of the work we studied the involvement in cancer of KRIT1, a protein known for its involvement in Cerebral Cavernous Malformation (CCM), a rare vascular disease typically found in the central nervous system. As KRIT1 in CCM induces characteristic similar to cancer including loss of cell junctions, improvement of migration and proliferation and new vessel formation, a tumor-suppressor like behaviour of KRIT1 has been hypothesized. Starting from this hypothesis, we first performed a bio-bank data analysis to find a correlation between KRIT1 and cancer and then we evaluated the expression levels of KRIT1 in human cancer specimens and its function in cancer cell lines. Taken together the data of this work contribute to increase the knowledge on the molecular mechanisms underlying the anticancer activities of two different natural derivatives and describe a new molecular pathway involved in cancer progression, thus providing scientific support for future therapies and new possible targets in the treatment of cancer.