Transforming Growth Factors α and β Are Essential for Modeling Cholangiocarcinoma Desmoplasia and Progression in a Three-Dimensional Organotypic Culture Model
| Autor: | Catherine I. Dumur, Jonathan A. Dranoff, Deanna J.W. Campbell, Miguel Á. Manzanares, Akihiro Usui, Michel Fausther, Alphonse E. Sirica, Gabrielle T. Maldonado |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Pathology medicine.medical_specialty Karyotype Cell Biology Pathology and Forensic Medicine Cholangiocarcinoma 03 medical and health sciences Stroma Transforming Growth Factor beta Tumor Cells Cultured medicine Animals Humans Myofibroblasts Anaplasia Cell growth Mesenchymal stem cell Regular Article Transforming Growth Factor alpha Coculture Techniques Rats Inbred F344 Desmoplasia Disease Models Animal Bile Ducts Intrahepatic 030104 developmental biology medicine.anatomical_structure Bile Duct Neoplasms Disease Progression Cancer research medicine.symptom Myofibroblast Transforming growth factor |
| Zdroj: | The American Journal of Pathology. 187:1068-1092 |
| ISSN: | 0002-9440 |
| DOI: | 10.1016/j.ajpath.2017.01.013 |
| Popis: | To gain insight into the cellular and molecular interactions mediating the desmoplastic reaction and aggressive malignancy of mass-forming intrahepatic cholangiocarcinoma (ICC), we modeled ICC desmoplasia and progression in vitro . A unique three-dimensional (3D) organotypic culture model was established; within a dilute collagen–type I hydrogel, a novel clonal strain of rat cancer-associated myofibroblasts (TDF SM ) was co-cultured with a pure rat cholangiocarcinoma cell strain (TDE CC ) derived from the same ICC type as TDF SM . This 3D organotypic culture model reproduced key features of desmoplastic reaction that closely mimicked those of the in situ tumor, as well as promoted cholangiocarcinoma cell growth and progression. Our results supported a resident liver mesenchymal cell origin of the TDF SM cells, which were not neoplastically transformed. Notably, 3D co-culturing of TDE CC cells with TDF SM cells provoked the formation of a dense fibrocollagenous stroma in vitro that was associated with significant increases in both proliferative TDF SM myofibroblastic cells and TDE CC cholangiocarcinoma cells accumulating within the gel matrix. This dramatic desmoplastic ICC-like phenotype, which was not observed in the TDE CC or TDF SM controls, was highly dependent on transforming growth factor (TGF)-β, but not promoted by TGF-α. However, TGF-α was determined to be a key factor for promoting cholangiocarcinoma cell anaplasia, hyperproliferation, and higher malignant grading in this 3D culture model of desmoplastic ICC. |
| Databáze: | OpenAIRE |
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