Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment.
In many organs, including the intestine and skin, cancers originate from cells of the stem or progenitor compartment. Despite its nomenclature, the cellular origin of hepatocellular carcinoma (HCC) remains elusive. In contrast to most organs, the liver lacks a defined stem cell population for organ maintenance. Previous studies suggest that both hepatocytes and facultative progenitor cells within the biliary compartment are capable of generating HCC. As HCCs with a progenitor signature carry a worse prognosis, understanding the origin of HCC is of clinical relevance. Here, we used complementary fate-tracing approaches to label the progenitor/biliary compartment and hepatocytes in murine hepatocarcinogenesis. In genotoxic and genetic models, HCCs arose exclusively from hepatocytes but never from the progenitor/biliary compartment. Cytokeratin 19-, A6- and α-fetoprotein-positive cells within tumors were hepatocyte derived. In summary, hepatocytes represent the cell of origin for HCC in mice, and a progenitor signature does not reflect progenitor origin, but dedifferentiation of hepatocyte-derived tumor cells.
Xueru
X
Mu
Regina
R
Español-Suñer
Ingmar
I
Mederacke
Silvia
S
Affò
Rita
R
Manco
Christine
C
Sempoux
Frédéric P
FP
Lemaigre
Arlind
A
Adili
Detian
D
Yuan
Achim
A
Weber
Kristian
K
Unger
Mathias
M
Heikenwälder
Isabelle A
IA
Leclercq
Robert F
RF
Schwabe
D000818:Animals; D001652:Bile Ducts / Q000166:cytology; D014408:Biomarkers, Tumor / Q000032:analysis; D002251:Carbon Tetrachloride / Q000633:toxicity; D002273:Carcinogens; D054337:Cell Dedifferentiation; D019070:Cell Lineage; D003043:Cocarcinogenesis; D055028:Comparative Genomic Hybridization; D004052:Diethylnitrosamine; D020869:Gene Expression Profiling; D017930:Genes, Reporter; D022781:Hepatocytes / Q000737:chemistry / Q000187:drug effects / Q000473:pathology*; D053539:Keratin-19 / Q000032:analysis; D008106:Liver Cirrhosis, Experimental / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000209:etiology / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000032:analysis; D014411:Neoplastic Stem Cells / Q000737:chemistry / Q000473:pathology*; D053495:Osteopontin / Q000032:analysis; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D011230:Precancerous Conditions / Q000139:chemically induced / Q000473:pathology; D013629:Tamoxifen / Q000494:pharmacology; D000509:alpha-Fetoproteins / Q000032:analysis
D014408:Biomarkers, Tumor; D002251:Carbon Tetrachloride; D002273:Carcinogens; D004052:Diethylnitrosamine; D053539:Keratin-19; D008840:Microfilament Proteins; D053495:Osteopontin; D051059:PTEN Phosphohydrolase; D013629:Tamoxifen; D000509:alpha-Fetoproteins; C506896:Spp1 protein, mouse; C487757:Pten protein, mouse; C485190:Twf1 protein, mouse