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Origin and Diversity of Fibroblastic Cells From Intrahepatic Cholangiocarcinoma
Author(s) -
Sirica Alphonse,
Usui Akihiro,
Campbell Deanna,
Dumur Catherine
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.45.5
Subject(s) - hepatic stellate cell , desmin , biology , fibroblast , vimentin , pathology , population , cell culture , microbiology and biotechnology , cell , cancer research , immunohistochemistry , immunology , endocrinology , genetics , medicine , environmental health
To elucidate cancer‐associated fibroblast (CAF) origins and diversity within intrahepatic cholangiocarcinoma (ICC), we analyzed the phenotypic, cytogenetic, gene expression profiles, growth properties, and select functions of two novel CAF cell strains (BDEsp‐TDF SM and BDEsp‐TDF DE ) along with those of a cholangiocarcinoma (CC) cell strain (BDEsp‐TDE CC ). Each cell strain was derived from desmoplastic CC formed in rat liver following bile duct inoculation of spontaneously‐transformed rat cholangiocytes. Unlike the CAF strains, BDEsp‐TDE CC exhibited anchorage‐independent growth, contained more numerous chromosomal aberrations, and was tumorigenic in rat liver. Both CAF strains exhibited similar, but distinct gene expression profiles compatible with their having a mesenchymal cell origin. TDF SM cells could be distinguished from TDF DE cells by being strongly immunoreactive for α‐smooth muscle actin (SM), positive for the portal fibroblast (PF) marker cofilin 1, negative for the hepatic stellate cell marker desmin (DE), and by producing significantly greater amounts of collagen type I. Co‐culturing BDE‐TDF SM with BDE‐TDE CC in a novel 3‐D culture model dramatically potentiated the production of collagen type I and greatly enhanced the numbers of both cytokeratin 19+/Ki‐67+ spheroid/ductal CC structures and TDF SM cells within the matrix when compared with TDE CC /TDF DE co‐culture or TDE CC , TDF SM , or TDE DE monocultures. The vast majority of CAFs accumulated within the stroma of analyzed rat and human ICC were further found to be SM+/DE‐ , with DE+ fibroblastic cells comprising only a small minority population. Our results suggest that SM+/cofilin1+/DE‐ CAFs promoting desmoplasia and ICC growth may largely be derived from PF.