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Cancer-Associated Fibroblasts Provide a Stromal Niche for Liver Cancer Organoids That Confers Trophic Effects and Therapy Resistance
- Source :
- Cellular and Molecular Gastroenterology and Hepatology, Cellular and Molecular Gastroenterology and Hepatology, 11(2), 407-431. Elsevier Inc.
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- 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.<br />Graphical abstract
- Subjects :
- 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
Subjects
Details
- ISSN :
- 2352345X
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Cellular and Molecular Gastroenterology and Hepatology
- Accession number :
- edsair.doi.dedup.....cbf0768c949717d28cf96aa15fc39b91
- Full Text :
- https://doi.org/10.1016/j.jcmgh.2020.09.003