Cancer-Associated Fibroblasts Provide a Stromal Niche for Liver Cancer Organoids That Confers Trophic Effects and Therapy Resistance
| Autor: | Zhouhong Ge, Ron Smits, Lucia Campos Carrascosa, Dave Sprengers, Jaap Kwekkeboom, Jan N. M. IJzermans, Guoying Zhou, Maikel P. Peppelenbosch, Ruby Lieshout, Ling Wang, Wanlu Cao, Lisanne Noordam, Pengfei Li, Qin Yang, Junhong Su, Jiaye Liu, Luc J. W. van der Laan, Meng Li, Buyun Ma, Monique M A Verstegen, Qiuwei Pan, Ruyi Zhang |
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| Přispěvatelé: | Gastroenterology & Hepatology, Surgery |
| Rok vydání: | 2021 |
| Předmět: |
FAP
fibroblast-associated protein 0301 basic medicine IGF insulin-like growth factor Liver Tumor Organoids Wnt wingless-related integration site Cell–Cell Contact Mice PCR polymerase chain reaction Liver Neoplasms Experimental 0302 clinical medicine Cancer-Associated Fibroblasts Tumor Cells Cultured Tumor Microenvironment Diethylnitrosamine Paracrine Effect OEM organoids expansion medium Original Research AFP α-fetoprotein Liver Neoplasms Gastroenterology ECM extracellular matrix Organoids EpCAM epithelial cell adhesion molecule NSG NOD scid γ mouse FACS fluorescence-activated cell sorter 030211 gastroenterology & hepatology Liver cancer medicine.drug Sorafenib CCA cholangiocarcinoma Carcinoma Hepatocellular Stromal cell Liver tumor Primary Cell Culture PBS phosphate-buffered saline Antineoplastic Agents Biology α-SMA α-smooth muscle actin Co-Culture PDGFRA platelet-derived growth factor receptor α 03 medical and health sciences Paracrine signalling SDG 3 - Good Health and Well-being 3D 3-dimensional Paracrine Communication OBM organoids basic medium medicine Animals Humans CAF cancer-associated fibroblast EGF epidermal growth factor Hepatology Cancer DEN N-nitrosodiethylamine medicine.disease CSC cancer stem cell Xenograft Model Antitumor Assays Coculture Techniques FGF fibroblast growth factor IL interleukin 030104 developmental biology Drug Resistance Neoplasm Culture Media Conditioned Cancer cell Cancer research TCGA The Cancer Genome Atlas DMEM Dulbecco’s modified Eagle medium 5-FU 5-fluorouracil HGF hepatocyte growth factor FCS fetal calf serum Stromal Cells HCC hepatocellular carcinoma |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, 11(2), 407-431. Elsevier Inc. |
| ISSN: | 2352-345X |
| Popis: | Background & Aims Cancer-associated fibroblasts (CAFs) play a key role in the cancer process, but the research progress is hampered by the paucity of preclinical models that are essential for mechanistic dissection of cancer cell–CAF interactions. Here, we aimed to establish 3-dimensional (3D) organotypic co-cultures of primary liver tumor–derived organoids with CAFs, and to understand their interactions and the response to treatment. Methods Liver tumor organoids and CAFs were cultured from murine and human primary liver tumors. 3D co-culture models of tumor organoids with CAFs and Transwell culture systems were established in vitro. A xenograft model was used to investigate the cell–cell interactions in vivo. Gene expression analysis of CAF markers in our hepatocellular carcinoma cohort and an online liver cancer database indicated the clinical relevance of CAFs. Results To functionally investigate the interactions of liver cancer cells with CAFs, we successfully established murine and human 3D co-culture models of liver tumor organoids with CAFs. CAFs promoted tumor organoid growth in co-culture with direct cell–cell contact and in a Transwell system via paracrine signaling. Vice versa, cancer cells secrete paracrine factors regulating CAF physiology. Co-transplantation of CAFs with liver tumor organoids of mouse or human origin promoted tumor growth in xenograft models. Moreover, tumor organoids conferred resistance to clinically used anticancer drugs including sorafenib, regorafenib, and 5-fluorouracil in the presence of CAFs, or the conditioned medium of CAFs. Conclusions We successfully established murine and human 3D co-culture models and have shown robust effects of CAFs in liver cancer nurturing and treatment resistance. Graphical abstract |
| Databáze: | OpenAIRE |
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