Diversity of hepatocellular carcinoma clones bearing hematopoietic malignancies-related chromosomal translocation.
Interpatient heterogeneity of hepatocellular carcinoma has been in-depth addressed. Intrapatient heterogeneity is less known. Four clones were freshly isolated from an Edmondson grade I HCV-associated hepatocellular carcinoma. Biochemical approaches, functional assays and cytogenetics were used. Albumin inducibility was uncoupled from canonical cytokeratin profiles, suggesting pathological combinations of hepatospecific and biliary markers. Poor differentiation and TGFβ's proproliferative effect on all clones were observed. TGFβ, Interferon α and doxorubicin sensitivity levels were found highly heterogeneous. Progenitor and stem cells markers OV6 and EpCAM were mutually exclusively expressed. All clones were CD44+, while none expressed CD90, CD133, or CD117. Three clones displayed a liver progenitor OV6+ phenotype, and were susceptible to hepatocytic differentiation, among which one fibroblastoid clone displayed intrahepatic parenchymal engraftment capability. A fourth clone, the less motile, displayed a cancer stem cell EpCAM+ phenotype, was essentially β-catenin negative, and was as expected devoid of hepatocytic differentiation capability, yet the most sensitive to doxorubicin treatment. Cytogenetics evidenced in all clones a t(12;22)(p11;q11) translocation found in several myelodysplastic syndromes. All clones, that probably derive from EpCAM+ tumor cells, display aberrant E-cadherin cytosolic localization. Because of their diverse pathophysiolocal features, these freshly isolated, low population doubling-defined, HCC clones may provide novel opportunities to tackle HCC heterogeneity in a single patient background for therapy improvement purposes, especially regarding recently developed targeted strategies.
DevWeCan Laboratories of Excellence Network (Labex), Université de Lyon, Lyon Cancer Research Center, Inserm U1052-CNRS UMR5286, Lyon, France.
Romain
R
Parent
Marie-Laure
ML
Plissonnier
Brigitte
B
Bancel
Wan-Li
WL
Liao
Sylvie
S
Rumin
Remal
R
Asaad
Marianne
M
Till
Damien
D
Sanlaville
Fabien
F
Zoulim
Christian
C
Trépo
Marie-Jeanne
MJ
Marion
D000368:Aged; D000818:Animals; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor / Q000235:genetics; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D015197:Carcinogenicity Tests; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology*; D015815:Cell Adhesion Molecules; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation; D002999:Clone Cells; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D019337:Hematologic Neoplasms / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007621:Karyotyping; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology*; D008819:Mice, Nude; D013234:Stem Cells / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; C497483:CD44 protein, human; D015820:Cadherins; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D018960:Hyaluronan Receptors; D016212:Transforming Growth Factor beta; D051176:beta Catenin
HEPATOCELLULAR CARCINOMA; LIVER; PROGENITOR CELLS