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Stem Cell Factor-Based Identification and Functional Properties of In Vitro-Selected Subpopulations of Malignant Mesothelioma Cells


Blum, Walter; Pecze, László; Felley-Bosco, Emanuela; Wu, Licun; de Perrot, Marc; Schwaller, Beat (2017). Stem Cell Factor-Based Identification and Functional Properties of In Vitro-Selected Subpopulations of Malignant Mesothelioma Cells. Stem Cell Reports, 8(4):1005-1017.

Abstract

Malignant mesothelioma (MM) is an aggressive neoplasm characterized by a poor patient survival rate, because of rapid tumor recurrence following first-line therapy. Cancer stem cells (CSCs) are assumed to be responsible for initiating tumorigenesis and driving relapse after therapeutic interventions. CSC-enriched MM cell subpopulations were identified by an OCT4/SOX2 reporter approach and were characterized by (1) increased resistance to cisplatin, (2) increased sensitivity toward the FAK inhibitor VS-6063 in vitro, and (3) a higher tumor-initiating capacity in vivo in orthotopic xenograft and allograft mouse models. Overexpression of NF2 (neurofibromatosis 2, merlin), a tumor suppressor often mutated or lost in MM, did not affect proliferation and viability of CSC-enriched MM populations but robustly decreased the viability of reporter-negative cells. In contrast, downregulation of calretinin strongly decreased proliferation and viability of both populations. In summary, we have enriched and characterized a small MM cell subpopulation that bears the expected CSC characteristics.

Abstract

Malignant mesothelioma (MM) is an aggressive neoplasm characterized by a poor patient survival rate, because of rapid tumor recurrence following first-line therapy. Cancer stem cells (CSCs) are assumed to be responsible for initiating tumorigenesis and driving relapse after therapeutic interventions. CSC-enriched MM cell subpopulations were identified by an OCT4/SOX2 reporter approach and were characterized by (1) increased resistance to cisplatin, (2) increased sensitivity toward the FAK inhibitor VS-6063 in vitro, and (3) a higher tumor-initiating capacity in vivo in orthotopic xenograft and allograft mouse models. Overexpression of NF2 (neurofibromatosis 2, merlin), a tumor suppressor often mutated or lost in MM, did not affect proliferation and viability of CSC-enriched MM populations but robustly decreased the viability of reporter-negative cells. In contrast, downregulation of calretinin strongly decreased proliferation and viability of both populations. In summary, we have enriched and characterized a small MM cell subpopulation that bears the expected CSC characteristics.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Thoracic Surgery
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:11 April 2017
Deposited On:01 Feb 2018 09:01
Last Modified:19 Aug 2018 13:33
Publisher:Cell Press (Elsevier)
ISSN:2213-6711
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.stemcr.2017.02.005
PubMed ID:28285878
Project Information:
  • : FunderSNSF
  • : Grant ID31003A_130680
  • : Project TitleKnock-out mice for the calcium-binding proteins parvalbumin, calbindin D-28k and calretinin. Models for muscle and brain diseases.
  • : FunderSNSF
  • : Grant ID316030_139226
  • : Project TitleIncuCyte-based high throughput imaging-based platform for determination of cellular and molecular events in real time in cultured cells in vitro: application to nanomaterial studies, cancer and cardiovascular research
  • : FunderSNSF
  • : Grant IDCRSII3_147697
  • : Project TitleFrom asbestos-exposure to cancer: a systemic approach to detect loss of homeostatic control in the mesothelial environment

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