AUTHOR=Darai-Ramqvist Eva , Nilsonne Gustav , Flores-Staino Carmen , Hjerpe Anders , Dobra Katalin 

TITLE=Microenvironment-Dependent Phenotypic Changes in a SCID Mouse Model for Malignant Mesothelioma

JOURNAL=Frontiers in Oncology

VOLUME=3

YEAR=2013

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2013.00203

DOI=10.3389/fonc.2013.00203

ISSN=2234-943X

ABSTRACT=<p><bold>Background and Aims:</bold> 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.</p><p><bold>Methods:</bold> Xenografts were established and thoroughly characterized using a comprehensive immunohistochemical panel, array comparative genomic hybridization (aCGH) of chromosome 3, fluorescent <italic>in situ</italic> hybridization, and electron microscopy.</p><p><bold>Results:</bold> 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.</p><p><bold>Conclusion:</bold> 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.</p>