Novel organotypic culture model of cholangiocarcinoma progression.

ABSTRACT: AIM:? Recent studies have suggested that increased ?-smooth muscle-actin positive myofibroblastic cells (?-SMA positive CAF) in the desmoplastic stroma may relate to a more aggressive cancer and worse survival outcomes for intrahepatic cholangiocarcinoma (ICC) patients. To facilitate investigating cellular and molecular interactions between ?-SMA positive CAF and cholangiocarcinoma cells related to ICC progression, we developed a novel 3-D organotypic culture model of cholangiocarcinoma that more accurately mimics the stromal microenvironment, gene expression profile and select pathophysiological characteristics of desmoplastic ICC in vivo. METHODS:? This unique model was established by co-culturing within a type I collagen gel matrix, a strain of cholangiocarcinoma cells (derived from an ICC formed in syngeneic rat liver following bile duct inoculation of spontaneously-transformed rat cholangiocytes) with varying numbers of clonal ?-SMA positive CAF established from the same tumor type. RESULTS:? Cholangiocarcinoma cells and ?-SMA positive CAF in monoculture each exhibited cell-specific biomarker gene expression profiles characteristic of stromal myofibroblastic cell versus malignant cholangiocyte cell types. In comparison, the gene expression profile and histopathological characteristics exhibited by the organotypic co-culture closely resembled those of whole tissue samples of the parent orthotopic ICC. We further showed ?-SMA positive CAF to significantly enhance cholangiocarcinoma cell "ductal-like" growth and cancer cell migration/invasiveness in vitro, as well as to promote upregulated expression of select genes known to be associated with ICC invasion. CONCLUSION:? This novel organotypic model provides an important new resource for studying the effects of microenvironment on cholangiocarcinoma progression in vitro and may have potential as a preclinical model for identifying molecularly targeted therapies.

SUBMITTER: Campbell DJ 

PROVIDER: S-EPMC3416930 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature