Abstract
BackgroundCombined hepatocellular-cholangiocarcinoma (CHC) is a primary hepatic malignancy with heterogeneously combined histological features of putative hepatic progenitor cells (HPC) origin. We describe a mouse model that exhibits the heterogenous histological and phenotypic finding similar to human CHC.MethodsWe injected hepatoblasts isolated from p53−/− C57BL/6 mice into syngeneic wild-type pre-conditioned C57BL/6 mice. We confirmed that p53−/− murine hepatoblasts act as tumor-initiating cells (TICs) that generate CHC both in situ and within metastases. For comparative pathological study, 8 human cases of CHC with stem cell features were recruited by immunohistochemistry and multicolor fluorescence immunostaining.ResultsWe identified corresponding areas in murine tumors matching each WHO criteria-described subtype of human CHC. In both murine and human tumors, HPC-like cells in tumor nests and associated stem cell features/traits are suggested histologically to be the progenitor origin of the cancerConclusionsThe pathological characteristics of murine tumors recapitulate human CHC with stem cell features. These data provide additional comparative pathological evidence that CHC with stem cell features originate from HPCs and validate a model to study this cancer type in vivo.
Highlights
Combined hepatocellular-cholangiocarcinoma (CHC) is a primary hepatic malignancy with heterogeneously combined histological features of putative hepatic progenitor cells (HPC) origin
The debate whether hepatocellular carcinoma (HCC) arises from stem cells that undergo malignant transformation or alternatively from dedifferentiated, transformed mature hepatocytes continues [5], most evidence suggest that CHC arises from hepatic progenitor cells (HPC) [6, 7]
We studied tumor heterogeneity that developed after seeding tumorigenic hepatic progenitor cells trans-splenically into livers of inflammatory pre-conditioned syngeneic C57BL/6 mice [14]
Summary
Combined hepatocellular-cholangiocarcinoma (CHC) is a primary hepatic malignancy with heterogeneously combined histological features of putative hepatic progenitor cells (HPC) origin. Combined hepatocellular-cholangiocarcinoma (CHC) represents fewer than 3% of human primary liver malignancies. HPC-like tumor cells, identified as small, oval-shaped cells with hyperchromatic nuclei and scant cytoplasm, can frequently be found within CHC [8]. These HPC-like tumor cells are characterized by co-expression of multiple progenitor/ stem cell markers [9].
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