Abstract
BackgroundThe development and evaluation of new therapeutic approaches for malignant mesothelioma has been sparse due, in part, to lack of suitable tumor models.MethodsWe established primary mesothelioma cultures from pleural and ascitic fluids of five patients with advanced mesothelioma. Electron microscopy and immunohistochemistry (IHC) confirmed their mesothelial origin. Patient derived xenografts were generated by injecting the cells in nude or SCID mice, and malignant potential of the cells was analyzed by soft agar colony assay. Molecular profiles of the primary patient tumors, early passage cell cultures, and patient derived xenografts were assessed using mutational analysis, fluorescence in situ hybridization (FISH) analysis and IHC.ResultsPrimary cultures from all five tumors exhibited morphologic and IHC features consistent to those of mesothelioma cells. Mutations of BAP1 and CDKN2A were each detected in four tumors. BAP1 mutation was associated with the lack of expression of BAP1 protein. Three cell cultures, all of which were derived from BAP1 mutant primary tumors, exhibited anchorage independent growth and also formed tumors in mice, suggesting that BAP1 loss may enhance tumor growth in vivo. Both early passage cell cultures and mouse xenograft tumors harbored BAP1 mutations and CDKN2A deletions identical to those found in the corresponding primary patient tumors.ConclusionsThe mesothelioma patient derived tumor xenografts with mutational alterations that mimic those observed in patient tumors which we established can be used for preclinical development of novel drug regimens and for studying the functional aspects of BAP1 biology in mesothelioma.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1362-2) contains supplementary material, which is available to authorized users.
Highlights
The development and evaluation of new therapeutic approaches for malignant mesothelioma has been sparse due, in part, to lack of suitable tumor models
Primary mesothelioma cultures established from malignant effusions of patients with mesothelioma Table 1 summarizes characteristics, diagnosis and course of treatment of patients with malignant mesothelioma from whom the primary cultures were derived
We describe the establishment of primary mesothelioma cultures and patient derived tumor xenografts with mutational alterations that recapitulate those in the original patient tumors
Summary
The development and evaluation of new therapeutic approaches for malignant mesothelioma has been sparse due, in part, to lack of suitable tumor models. Mouse models generated via engraftment of primary human tumors into immunecompromised mouse models have become increasingly popular for preclinical testing of anticancer drugs. Their usefulness depends upon the preservation of biological and morphological characteristics of the primary tumors [5]. Many of the currently available mesothelioma cell lines do not form tumors in mice, and others have been propagated in culture for many passages, leading to various cytogenetic changes. These lines often do not show much similarity with the original tumors [6]
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