Development of a human three-dimensional organotypic skin-melanoma spheroid model for in vitro drug testing
Open Access
- 11 July 2013
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 4 (7), e719
- https://doi.org/10.1038/cddis.2013.249
Abstract
Despite remarkable efforts, metastatic melanoma (MM) still presents with significant mortality. Recently, mono-chemotherapies are increasingly replenished by more cancer-specific combination therapies involving death ligands and drugs interfering with cell signaling. Still, MM remains a fatal disease because tumors rapidly develop resistance to novel therapies thereby regaining tumorigenic capacity. Although genetically engineered mouse models for MM have been developed, at present no model is available that reliably mimics the human disease and is suitable for studying mechanisms of therapeutic obstacles including cell death resistance. To improve the increasing requests on new therapeutic alternatives, reliable human screening models are demanded that translate the findings from basic cellular research into clinical applications. By developing an organotypic full skin equivalent, harboring melanoma tumor spheroids of defined sizes we have invented a cell-based model that recapitulates both the 3D organization and multicellular complexity of an organ/tumor in vivo but at the same time accommodates systematic experimental intervention. By extending our previous findings on melanoma cell sensitization toward TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) by co-application of sublethal doses of ultraviolet-B radiation (UVB) or cisplatin, we show significant differences in the therapeutical outcome to exist between regular two-dimensional (2D) and complex in vivo-like 3D models. Of note, while both treatment combinations killed the same cancer cell lines in 2D culture, skin equivalent-embedded melanoma spheroids are potently killed by TRAIL+cisplatin treatment but remain almost unaffected by the TRAIL+UVB combination. Consequently, we have established an organotypic human skin-melanoma model that will facilitate efforts to improve therapeutic outcomes for malignant melanoma by providing a platform for the investigation of cytotoxic treatments and tailored therapies in a more physiological setting.Keywords
This publication has 45 references indexed in Scilit:
- Genomic responses in mouse models poorly mimic human inflammatory diseasesProceedings of the National Academy of Sciences of the United States of America, 2013
- Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitorsNature, 2012
- Improved Survival with Vemurafenib in Melanoma with BRAF V600E MutationThe New England Journal of Medicine, 2011
- A Simple Hanging Drop Cell Culture Protocol for Generation of 3D SpheroidsJournal of Visualized Experiments, 2011
- Inhibition of Mutated, Activated BRAF in Metastatic MelanomaThe New England Journal of Medicine, 2010
- A Temporarily Distinct Subpopulation of Slow-Cycling Melanoma Cells Is Required for Continuous Tumor GrowthCell, 2010
- Final Version of 2009 AJCC Melanoma Staging and ClassificationJournal of Clinical Oncology, 2009
- Melanoma Stem Cells: The Dark Seed of MelanomaJournal of Clinical Oncology, 2008
- Human agonistic TRAIL receptor antibodies Mapatumumab and Lexatumumab induce apoptosis in malignant mesothelioma and act synergistically with cisplatinMolecular Cancer, 2007
- Human Melanoma Progression in Skin Reconstructs: Biological Significance of bFGFThe American Journal of Pathology, 2000