title: Pleural mesothelioma side populations have a precursor phenotype.
abstract: DyeCycleViolet was used to set up the side population (SP) functional assay aimed at identifying subpopulations of malignant pleural mesothelioma (MPM) tumor cells with chemoresistance phenotype associated with ABCG2 transporter activity. Self-renewal, chemoresistance and tumorigenicity were tested for SP and non-side population (NSP) cells. Tumors were characterized by mesothelin, calretinin, N-cadherin, D2-40 and Wilms tumor 1 (WT1) immunohistochemistry. Surface expression of mesenchymal stem cell markers CD90, CD73 and CD105 was investigated in SP and NSP cells. We identified SP cells with self-renewal properties and increased chemoresistance in MPM cell lines and tumor-derived primary cell cultures. Compared with the non-SP fraction (NSP), the SP fraction led to the development of tumors including cells with mesothelium precursor phenotype characterized by mesenchymal morphology, being WT1 negative but cytoplasmic D2-40 positive and having a tendency of increased tumorigenicity. The same phenotypic shift was observed in patients with relapsing tumors after chemotherapy. Furthermore, the SP cells were enriched in CD105(-)(/low) expressing cells, which were small sized and had increased tumorigenicity compared with CD105(high) cells. Taken together, our results support the hypothesis that MPM CD105(-)(/low), chemoresistant small sized SP cells may constitute the cellular pool out of which recurrence develops. Further characterization of mechanisms of chemoresistance and self-renewal should lead to targets specific for this subpopulation in MPM patients.
authors: Laboratory of Molecular Oncology, Clinic of Oncology, University Hospital Zürich, Haeldeliweg 4, 8044 Zurich, Switzerland.
authors: Claudia
authors: C
authors: Frei
authors: Isabelle
authors: I
authors: Opitz
authors: Alex
authors: A
authors: Soltermann
authors: Bruno
authors: B
authors: Fischer
authors: Ubiratan
authors: U
authors: Moura
authors: Hubert
authors: H
authors: Rehrauer
authors: Walter
authors: W
authors: Weder
authors: Rolf
authors: R
authors: Stahel
authors: Emanuela
authors: E
authors: Felley-Bosco
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D019008:Drug Resistance, Neoplasm; D000071063:Endoglin; D018922:HL-60 Cells; D006801:Humans; D000090204:Mesothelin; D008654:Mesothelioma / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D010641:Phenotype; D010997:Pleural Neoplasms / Q000188:drug therapy / Q000473:pathology*; D011956:Receptors, Cell Surface / Q000032:analysis; D025721:WT1 Proteins / Q000032:analysis
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; C000715528:Msln protein, mouse; D011956:Receptors, Cell Surface; D025721:WT1 Proteins; D000090204:Mesothelin