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Updated: Mar 21, 2026
A 3D Organotypic Melanoma Spheroid Skin Model
Published on: May 18, 2018
The barrier function of organotypic non-melanoma skin cancer models
Christian Zoschke1, Martina Ulrich2, Michaela Sochorová3
1Institute for Pharmacy, Freie Universität Berlin, Königin-Luise-Str. 2+4, 14195 Berlin, Germany.
Abstract:
Non-melanoma skin cancer (NMSC) is the most frequent human cancer with continuously rising incidences worldwide. Herein, we investigated the molecular basis for the impaired skin barrier function of organotypic NMSC models. We unraveled disturbed epidermal differentiation by reflectance confocal microscopy and histopathological evaluation. While the presence of claudin-4 and occludin were distinctly reduced, zonula occludens protein-1 was more wide-spread, and claudin-1 was heterogeneously distributed within the NMSC models compared with normal reconstructed human skin. Moreover, the cancer altered stratum corneum lipid packing and profile with decreased cholesterol content, increased phospholipid amount, and altered ceramide subclasses. These alterations contributed to increased surface pH and to 1.5 to 2.6-fold enhanced caffeine permeability of the NMSC models. Three topical applications of ingenol mebutate gel (0.015%) caused abundant epidermal cell necrosis, decreased Ki-67 indices, and increased lactate dehydrogenase activity. Taken together, our study provides new biological insights into the microenvironment of organotypic NMSC models, improves the understanding of the disease model by revealing causes for impaired skin barrier function in NMSC models at the molecular level, and fosters human cell-based approaches in preclinical drug evaluation.
Insights
Non-melanoma skin cancer (NMSC) models show impaired skin barrier function due to altered epidermal differentiation and lipid profiles. These changes increase permeability, offering insights into NMSC disease models.
Area of Science:
- Dermatology
- Molecular Biology
- Cancer Research
Background:
- Non-melanoma skin cancer (NMSC) is the most common human cancer globally.
- Rising incidences necessitate better understanding and models of NMSC.
- Skin barrier dysfunction is a key aspect of NMSC pathogenesis.
Purpose of the Study:
- Investigate the molecular basis of impaired skin barrier function in organotypic NMSC models.
- Characterize alterations in epidermal differentiation and lipid composition.
- Evaluate the impact of these changes on skin barrier permeability.
Main Methods:
- Organotypic NMSC models and normal reconstructed human skin.
- Reflectance confocal microscopy and histopathological evaluation.
- Analysis of tight junction proteins (claudins, occludin, ZO-1).
- Stratum corneum lipid profiling and surface pH measurement.
- Caffeine permeability assays.
- Assessment of ingenol mebutate gel effects.
Main Results:
- Disturbed epidermal differentiation observed in NMSC models.
- Reduced claudin-4 and occludin, altered zonula occludens protein-1 and claudin-1 distribution.
- Altered stratum corneum lipids (decreased cholesterol, increased phospholipids, changed ceramides).
- Increased surface pH and 1.5 to 2.6-fold enhanced caffeine permeability.
- Ingenol mebutate gel induced epidermal necrosis and altered cellular markers.
Conclusions:
- NMSC models exhibit molecular changes leading to impaired skin barrier function.
- Alterations in tight junctions and lipids are key contributors to barrier defects.
- These findings enhance understanding of NMSC models and support their use in preclinical drug evaluation.
