In the past decade it became increasingly clear that tumor heterogeneity represents one of the major problems for cancer treatment, also in prostate cancer. The identification of the molecular... Show moreIn the past decade it became increasingly clear that tumor heterogeneity represents one of the major problems for cancer treatment, also in prostate cancer. The identification of the molecular properties of highly aggressive cells (Cancer Stem Cells, CSCs) dispersed within the tumor represents a challenge for the identification of new efficient therapies. In most of the cases, current treatments are indeed successful in eradicating the primary tumor. However, the clinical evidence of relapse and the occurrence of therapy resistance, suggest the presence of subpopulation of cells within the tumor, that can survive such treatments and can perpetuate the cancer. In this thesis we investigated the molecular properties of selected highly aggressive CSCs and indentified novel modulators responsible for the maintenance of their aggressive behavior. Collectively, the studies described in this thesis have increased our insights into the molecular properties of highly metastatic and tumorigenic prostate cancer stem-like cells and provided new targets for possible diagnostic and therapeutic applications. Show less
Cancer and fibrosis are devastating diseases of high mortality rate and with limited curative therapies available. A better understanding of the biological drivers of these diseases is fundamental... Show moreCancer and fibrosis are devastating diseases of high mortality rate and with limited curative therapies available. A better understanding of the biological drivers of these diseases is fundamental in order to develop effective therapeutics. At the molecular level, signaling pathways control cell growth, differentiation or apoptosis during development and adult life of the organism ensuring homeostasis. Paradoxically, the same signals are often implicated or even drive disease progression. One of the signaling pathways with key regulatory functions in homeostasis, tissue fibrosis and cancer in many organs is the TGFβ/BMP pathway. In this thesis we addressed the role and therapeutic potential of TGFβ/BMP pathway inhibition using different drug compounds that are currently towards the clinic or being tested in clinical trials. Three distinct types of inhibitors were used; small molecule inhibitors of the ALK4, 5 and 7 TGFβ receptor kinases, an antisense oligonucleotide interfering with ALK5 mRNA splicing and an ALK1 ligand trap; a peptide that contains the extracellular domain of ALK1 fused to Fc and sequesters BMP9 and BMP10. These inhibitors were used in an ex vivo human fibrosis model and in vivo mouse models of various human diseases (acute liver failure/ liver regeneration, Dupuytren's fibrosis) and cancer (prostate, liver). Show less
