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CRIPTO promotes an aggressive tumour phenotype and resistance to treatment in hepatocellular carcinoma
The Journal of pathology, 2018-07, Vol.245 (3), p.297-310
Karkampouna, Sofia
van der Helm, Danny
Gray, Peter C
Chen, Lanpeng
Klima, Irena
Grosjean, Joël
Burgmans, Mark C
Farina‐Sarasqueta, Arantza
Snaar‐Jagalska, Ewa B
Stroka, Deborah M
Terracciano, Luigi
van Hoek, Bart
Schaapherder, Alexander F
Osanto, Susan
Thalmann, George N
Verspaget, Hein W
Coenraad, Minneke J
Kruithof‐de Julio, Marianna
2018
Details
Autor(en) / Beteiligte
Karkampouna, Sofia
van der Helm, Danny
Gray, Peter C
Chen, Lanpeng
Klima, Irena
Grosjean, Joël
Burgmans, Mark C
Farina‐Sarasqueta, Arantza
Snaar‐Jagalska, Ewa B
Stroka, Deborah M
Terracciano, Luigi
van Hoek, Bart
Schaapherder, Alexander F
Osanto, Susan
Thalmann, George N
Verspaget, Hein W
Coenraad, Minneke J
Kruithof‐de Julio, Marianna
Titel
CRIPTO promotes an aggressive tumour phenotype and resistance to treatment in hepatocellular carcinoma
Ist Teil von
The Journal of pathology, 2018-07, Vol.245 (3), p.297-310
Ort / Verlag
Chichester, UK: John Wiley & Sons, Ltd
Erscheinungsjahr
2018
Link zum Volltext
Quelle
Wiley Online Library Journals Frontfile Complete
Beschreibungen/Notizen
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 tumourigenesis 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 that sorafenib resistance may be circumvented by inhibition of the CRIPTO pathway. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Sprache
Englisch
Identifikatoren
ISSN: 0022-3417
eISSN: 1096-9896
DOI: 10.1002/path.5083
Titel-ID: cdi_proquest_miscellaneous_2020489282
Format
–
Schlagworte
Animal models
,
Cancer
,
Cell migration
,
Cell proliferation
,
Cirrhosis
,
Combinatorial analysis
,
CRIPTO
,
Cripto protein
,
Doxorubicin
,
GRP78
,
Hepatocellular carcinoma
,
HepG2
,
Liver cancer
,
liver cirrhosis
,
Medical treatment
,
Mesenchyme
,
neoplasia
,
organoids
,
Patients
,
patient‐derived xenografts
,
Phenotypes
,
Prognosis
,
sorafenib resistance
,
Stem cells
,
Three dimensional models
,
Tumorigenesis
,
Tumors
,
Xenografts
,
zebrafish xenograft
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