Microenvironment-Dependent Phenotypic Changes in a SCID Mouse Model for Malignant Mesothelioma.
OBJECTIVE
Malignant mesothelioma is an aggressive, therapy-resistant tumor. Mesothelioma cells may assume an epithelioid or a sarcomatoid phenotype, and presence of sarcomatoid cells predicts poor prognosis. In this study, we investigated differentiation of mesothelioma cells in a xenograft model, where mesothelioma cells of both phenotypes were induced to form tumors in severe combined immunodeficiency mice.


METHODS
Xenografts were established and thoroughly characterized using a comprehensive immunohistochemical panel, array comparative genomic hybridization (aCGH) of chromosome 3, fluorescent in situ hybridization, and electron microscopy.


RESULTS
Epithelioid and sarcomatoid cells gave rise to xenografts of similar epithelioid morphology. While sarcomatoid-derived xenografts had higher growth rates, the morphology and expression of differentiation-related markers was similar between xenografts derived from both phenotypes. aCGH showed a convergent genotype for both xenografts, resembling the original aggressive sarcomatoid cell sub-line.


CONCLUSIONS
Human mesothelioma xenografts from sarcomatoid and epithelioid phenotypes converged to a similar differentiation state, and genetic analyses suggested that clonal selection in the mouse microenvironment was a major contributing factor. This thoroughly characterized animal model can be used for further studies of molecular events underlying tumor cell differentiation.
Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet , Stockholm , Sweden ; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet , Stockholm , Sweden.
Eva
E
Darai-Ramqvist
Gustav
G
Nilsonne
Carmen
C
Flores-Staino
Anders
A
Hjerpe
Katalin
K
Dobra
SCID mice; chromosome 3; differentiation; epithelioid; mesothelioma; sarcomatoid