PUBLICATION
CRIPTO promotes an aggressive tumour phenotype and resistance to treatment in hepatocellular carcinoma
- Authors
- Karkampouna, S., van der Helm, D., Gray, P.C., Chen, L., Klima, I., Grosjean, J., Burgmans, M.C., Farina-Sarasqueta, A., Snaar-Jagalska, E.B., Stroka, D.M., Terracciano, L., van Hoek, B., Schaapherder, A.F., Osanto, S., Thalmann, G.N., Verspaget, H.W., Coenraad, M.J., Kruithof-de Julio, M.
- ID
- ZDB-PUB-180401-2
- Date
- 2018
- Source
- The Journal of pathology 245(3): 297-310 (Journal)
- Registered Authors
- Snaar-Jagalska, Ewa B.
- Keywords
- CRIPTO, GRP78, HepG2, hepatocellular carcinoma, liver cirrhosis, neoplasia, patient-derived xenografts, zebrafish xenograft, organoids, sorafenib resistance
- MeSH Terms
-
- Aged
- Aged, 80 and over
- Animals
- Antibiotics, Antineoplastic/pharmacology
- Antineoplastic Agents/pharmacology*
- Carcinoma, Hepatocellular/drug therapy*
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism*
- Carcinoma, Hepatocellular/pathology
- Cell Movement/drug effects
- Cell Proliferation/drug effects
- Doxorubicin/pharmacology
- Drug Resistance, Neoplasm*/genetics
- Epithelial-Mesenchymal Transition/drug effects
- Female
- GPI-Linked Proteins/antagonists & inhibitors
- GPI-Linked Proteins/genetics
- GPI-Linked Proteins/metabolism*
- Gene Expression Regulation, Neoplastic
- Hep G2 Cells
- Humans
- Intercellular Signaling Peptides and Proteins/genetics
- Intercellular Signaling Peptides and Proteins/metabolism*
- Liver Neoplasms/drug therapy*
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism*
- Liver Neoplasms/pathology
- Male
- Mice, Inbred NOD
- Middle Aged
- Neoplasm Proteins/antagonists & inhibitors
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism*
- Neoplastic Stem Cells/drug effects
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Peptides/pharmacology
- Phenotype
- Protein Kinase Inhibitors/pharmacology*
- Signal Transduction/drug effects
- Sorafenib/pharmacology*
- Tissue Culture Techniques
- Xenograft Model Antitumor Assays
- Zebrafish
- PubMed
- 29604056 Full text @ J. Pathol.
Citation
Karkampouna, S., van der Helm, D., Gray, P.C., Chen, L., Klima, I., Grosjean, J., Burgmans, M.C., Farina-Sarasqueta, A., Snaar-Jagalska, E.B., Stroka, D.M., Terracciano, L., van Hoek, B., Schaapherder, A.F., Osanto, S., Thalmann, G.N., Verspaget, H.W., Coenraad, M.J., Kruithof-de Julio, M. (2018) CRIPTO promotes an aggressive tumour phenotype and resistance to treatment in hepatocellular carcinoma. The Journal of pathology. 245(3):297-310.
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Despite increasing treatment options for this disease, prognosis remains poor. CRIPTO (TDGF1) protein is expressed at high levels in several human tumours and promotes oncogenic phenotype. Its expression has been correlated to poor prognosis in HCC. In this study, we aimed to elucidate the basis for the effects of CRIPTO in HCC. We investigated CRIPTO expression levels in three cohorts of clinical cirrhotic and HCC specimens. We addressed the role of CRIPTO in hepatic tumorigenesis using Cre-loxP-controlled lentiviral vectors expressing CRIPTO in cell line derived xenografts. Responses to standard treatments (sorafenib, doxorubicin) were assessed directly on xenograft-derived ex vivo tumour slices. CRIPTO-overexpressing patient derived xenografts were established and used for ex vivo drug response assays. The effects of sorafenib and doxorubicin treatment in combination with a CRIPTO pathway inhibitor were tested in ex vivo cultures of xenograft models and 3D cultures. CRIPTO protein was found highly expressed in human cirrhosis and hepatocellular carcinoma specimens but not in those of healthy participants. Stable overexpression of CRIPTO in human HepG2 cells caused epithelial-to-mesenchymal transition, increased expression of cancer stem cell markers, and enhanced cell proliferation and migration. HepG2-CRIPTO cells formed tumours when injected into immune-compromised mice, whereas HepG2 cells lacking stable CRIPTO overexpression did not. High level CRIPTO expression in xenograft models was associated with resistance to sorafenib, which could be modulated using a CRIPTO pathway inhibitor in ex vivo tumour slices. Our data suggest that a subgroup of CRIPTO-expressing HCC patients may benefit from a combinatorial treatment scheme and sorafenib resistance may be circumvented by inhibition of the CRIPTO pathway.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping