Cholangiocytes: Cell transplantation

Background:Due to significant limitations to the access to orthotropic liver transplantation, cell therapies forliver diseases have gained large interest worldwide.Scope of review:To revise current literature dealing with cell therapy for liver diseases. We discussed the ad-vantages and pitfalls of the different cell sources tested so far in clinical trials and the rationale underlying thepotential benefits of transplantation of human biliary tree stem cells (hBTSCs).Major conclusions:Transplantation of adult hepatocytes showed transient benefits but requires immune-sup-pression that is a major pitfall in patients with advanced liver diseases. Mesenchymal stem cells and hemato-poietic stem cells transplanted into patients with liver diseases are not able to replace resident hepatocytes butrather they target autoimmune or inflammatory processes into the liver. Stem cells isolated from fetal or adultliver have been recently proposed as alternative cell sources for advanced liver cirrhosis and metabolic liverdisease. We demonstrated the presence of multipotent cells expressing a variety of endodermal stem cell markersin (peri)-biliary glands of bile ducts in fetal or adult human tissues, and in crypts of gallbladder epithelium. Inthefirst cirrhotic patients treated in our center with biliary tree stem cell therapy, we registered no adverse eventbut significant benefits.General significance:The biliary tree stem cell could represent the ideal cell source for the cell therapy of liverdiseases. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by JesusBanales, Marco Marzioni, Nicholas LaRusso and Peter Jansen

Intrahepatic cholangiocarcinoma: review and update

Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies that could develop at any level from the biliary tree. CCA is currently classified into intrahepatic (iCCA), perihilar and distal on the basis of its anatomical location. Of note, these three CCA subtypes have common features but also important inter-tumor and intra-tumor differences that can affect the pathogenesis and outcome. A unique feature of iCCA is that it recognizes as origin tissues, the hepatic parenchyma or large intrahepatic and extrahepatic bile ducts, which are furnished by two distinct stem cell niches, the canals of Hering and the peribiliary glands, respectively. The complexity of iCCA pathogenesis highlights the need of a multidisciplinary, translational and systemic approach to this malignancy. This review will focus on the advances of iCCA epidemiology, histo-morphology, risk factors, molecular pathogenesis, revealing the existence of multiple subsets of iCCA

cholangiocarcinomas new insights from the discovery of stem cell niches in peribiliary glands of the biliary tree

Peribiliary glands (PBGs) are located in the large intrahepatic and extrahepatic bile ducts. Although they were described many years ago, their functions have been elucidated only in the last couple of years when our group demonstrated that PBGs are niches of multipotent stem/progenitor cells of endodermal origin. These cells express genes of multipotency and can be rapidly differentiatedin vitrointo hepatocytes, cholangiocytes, and endocrine pancreatic cells. PBGs share common features, in terms of stem/progenitor cell niches, with pancreatic duct glands and colon crypts, glandular structures representing in the adult life the endodermal remnants of fetal life. PBG stem/progenitor cells participate in the renewal of surface biliary epithelium and are active players in chronic pathologies of the biliary tree as well as in cholangiocarcinomas (CCA). Specifically, a large amount of recent evidence indicates that the pure mucin-CCA originates from PBGs; this could explain the similarities with pancreatic ductal adenocarcinoma and colorectal cancer, which also originate from transformed gland cells. In this paper, we summarized our recent findings concerning structure and functions of PBGs with the implications for liver pathophysiology and, specifically, for cancers of the biliary tree

Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types

Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA), and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over-representation, recurrent loss of function (tumor suppressor-like), or hotspot mutation profile (oncogene-like). Furthermore, RNA sequencing analysis revealed altered splicing events associated with selected splicing factor mutations. In addition, we were able to identify common gene pathway profiles associated with the presence of these mutations. Our analysis suggests that somatic alteration of genes involved in the RNA-splicing process is common in cancer and may represent an underappreciated hallmark of tumorigenesis

Transplantation of human fetal biliary tree stem/progenitor cells into two patients with advanced liver cirrhosis.

Efforts to identify cell sources and approaches for cell therapy of liver diseases are ongoing, taking into consideration the limits recognized for adult liver tissue and for other forms of stem cells. In the present study, we described the first procedure of via hepatic artery transplantation of human fetal biliary tree stem cells in patients with advanced cirrhosis.MethodsThe cells were immune-sorted from human fetal biliary tree by protocols in accordance with current good manufacturing practice (cGMP) and extensively characterized. Two patients with advanced cirrhosis (Child-Pugh C) have been submitted to the procedure and observed through a 12 months follow-up.ResultsThe resulting procedure was found absolutely safe. Immuno-suppressants were not required, and the patients did not display any adverse effects correlated with cell transplantation or suggestive of immunological complications. From a clinical point of view, both patients showed biochemical and clinical improvement during the 6 month follow-up (Table1), and the second patient maintained a stable improvement for 12 months.ConclusionThis report represents proof of the concept that the human fetal biliary tree stem cells are a suitable and large source for cell therapy of liver cirrhosis. The isolation procedure can be carried out under cGMP conditions and, finally, the infusion procedure is easy and safe for the patients. This represents the basis for forthcoming controlled clinical trials

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin