Extracellular Vesicles in Hepatobiliary Malignancies

Primary hepatobiliary malignancies include a heterogeneous group of cancers with dismal prognosis, among which hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and hepatoblastoma (HB) stand out. These tumors mainly arise from the malignant transformation of hepatocytes, cholangiocytes (bile duct epithelial cells) or hepatoblasts (embryonic liver progenitor cells), respectively. Early diagnosis, prognosis prediction and effective therapies are still a utopia for these diseases. Extracellular vesicles (EVs) are small membrane-enclosed spheres secreted by cells and present in biological fluids. They contain multiple types of biomolecules, such as proteins, RNA, DNA, metabolites and lipids, which make them a potential source of biomarkers as well as regulators of human pathobiology. In this review, the role of EVs in the pathogenesis of hepatobiliary cancers and their potential usefulness as disease biomarkers are highlighted. Moreover, the therapeutic value of EV regulation is discussed and future directions on basic and clinical research are indicated.Spanish Ministries of Economy and Competitiveness [JB (FIS PI12/00380, FIS PI15/01132 and Miguel Servet Programme CON14/00129); MP (FIS PI14/00399, FIS PI17/00022) and Ramon y Cajal Programme RYC-2015-17755] cofinanced by Fondo Europeo de Desarrollo Regional (FEDER); ISCIII [CIBERehd: JB, LB, and MP], Spain; Diputacion Foral Gipuzkoa (JB: DFG15/010, DFG16/004), BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/BD to JB); Department of Health of the Basque Country (JB: 2013111173 and 2017111010; MP: 2015111100), and AECC Scientific Foundation (JB). AL and PO were funded by the Basque Government

Extracellular Vesicles in Hepatobiliary Malignancies

Primary hepatobiliary malignancies include a heterogeneous group of cancers with dismal prognosis, among which hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and hepatoblastoma (HB) stand out. These tumors mainly arise from the malignant transformation of hepatocytes, cholangiocytes (bile duct epithelial cells) or hepatoblasts (embryonic liver progenitor cells), respectively. Early diagnosis, prognosis prediction and effective therapies are still a utopia for these diseases. Extracellular vesicles (EVs) are small membrane-enclosed spheres secreted by cells and present in biological fluids. They contain multiple types of biomolecules, such as proteins, RNA, DNA, metabolites and lipids, which make them a potential source of biomarkers as well as regulators of human pathobiology. In this review, the role of EVs in the pathogenesis of hepatobiliary cancers and their potential usefulness as disease biomarkers are highlighted. Moreover, the therapeutic value of EV regulation is discussed and future directions on basic and clinical research are indicated

Epigenetic deregulation of the histone methyltransferase KMT5B contributes to malignant transformation in glioblastoma

Glioblastoma multiforme (GBM) is the most common and aggressive type of brain tumor in adulthood. Epigenetic mechanisms are known to play a key role in GBM although the involvement of histone methyltransferase KMT5B and its mark H4K20me2 has remained largely unexplored. The present study shows that DNA hypermethylation and loss of DNA hydroxymethylation is associated with KMT5B downregulation and genome-wide reduction of H4K20me2 levels in a set of human GBM samples and cell lines as compared with non-tumoral specimens. Ectopic overexpression of KMT5B induced tumor suppressor-like features in vitro and in a mouse tumor xenograft model, as well as changes in the expression of several glioblastoma-related genes. H4K20me2 enrichment was found immediately upstream of the promoter regions of a subset of deregulated genes, thus suggesting a possible role for KMT5B in GBM through the epigenetic modulation of key target cancer genes.This research was funded by the Health Institute Carlos III (Plan Nacional de I+D+I) cofounding FEDER (PI15/00892 and PI18/01527 to MF and AF); the Government of the Principality of Asturias PCTI-Plan de Ciencia, Tecnología e Innovación de Asturias co-funding 2018–2022/FEDER (IDI/2018/146 to MF); AECC (PROYE18061FERN to MF); FGCSIC (0348_CIE_6_E to MF); Severo Ochoa Program BP17-165 to PS-O and BP17-114 to RP); the Ministry of Economy and Competitiveness of Spain (VL, Juan de la Cierva fellowship IJCI-2015-23316; JT, Juan de la Cierva fellowship FJCI-2015-26965); FICYT (AC and MG); FINBA-ISPA (VL); and IUOPA (VL and CM). The IUOPA is supported by the Obra Social Cajastur-Liberbank, Spain.Peer reviewe