Titolo della tesi: The role of β-Hydroxy-β-methyl butyrate (HMB) in glioma growth suppression in mice
Glioblastoma (GBM) represents one of the most aggressive malignancies of the central nervous system (CNS), characterized by limited therapeutic options and high recurrence rate. One of the factors contributing to the poor prognosis of glioblastoma is its highly invasive nature, which enables glioblastoma cells to migrate and infiltrate adjacent healthy brain tissues. This diffuse infiltration complicates efforts to achieve complete surgical resection, thereby limiting the effectiveness of surgical interventions and contributing to the tumor's recurrence and resistance to treatment. This invasive behavior is driven by a complex interplay of genetic, molecular, and environmental factors that regulate cytoskeletal dynamics, cell adhesion, and extracellular matrix degradation. Previous studies reveal that the gut microbiota plays a significant role in glioblastoma progression through the modulation of neurotransmitters and immune responses, and also gut microbiome can influence the
growth of gliomas by altering the composition of microbes and metabolites, impacting tumor development. Previously we have shown that gut microbiota plays an important role in the gut-brain axis both in physiological and glioma conditions. Here we show that in the presence of glioma, fecal metabolite β-hydroxy-β-methylbutyrate (HMB) was significantly reduced compared to the same mice before tumor cell inoculation. Of note, HMB administration reduces tumor growth and proliferation in carcinoma cells. To understand whether HMB could be effective also against glioma cells, we first demonstrated in vitro that HMB directly inhibits proliferation in both mouse and human glioblastoma cell lines and inhibits glioma cell basal cell migration and FBS-induced invasion. In in vivo studies, oral gavage of HMB to glioma-bearing mice resulted in a significant reduction in tumour volume compared to control mice, suggesting that this leucine metabolite, which is produced in the gut, may have an anti-tumour role in glioma.
Keywords: Glioblastoma, Gut-Brain Axis, Metabolites, HMB, Proliferation, Migration