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Impact of Human Adipose Tissue-Derived Stem Cells on Malignant Melanoma Cells in An In Vitro Co-culture Model

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Abstract

This study focuses on the interactions of human adipose tissue-derived stem cells (ADSCs) and malignant melanoma cells (MMCs) with regard to future cell-based skin therapies. The aim was to identify potential oncological risks as ADSCs could unintentionally be sited within the proximity of the tumor microenvironment of MMCs. An indirect co-culture model was used to analyze interactions between ADSCs and four different established melanoma cell lines (G-361, SK-Mel-5, MeWo and A2058) as well as two low-passage primary melanoma cell cultures (M1 and M2). Doubling time, migration and invasion, angiogenesis, quantitative real-time PCR of 229 tumor-associated genes and multiplex protein assays of 20 chemokines and growth factors and eight matrix metalloproteinases (MMPs) were evaluated. Co-culture with ADSCs significantly increased migration capacity of G-361, SK-Mel-5, A2058, MeWo and M1 and invasion capacity of G-361, SK-Mel-5 and A2058 melanoma cells. Furthermore, conditioned media from all ADSC-MMC-co-cultures induced tube formation in an angiogenesis assay in vitro. Gene expression analysis of ADSCs and MMCs, especially of low-passage melanoma cell cultures, revealed an increased expression of various genes with tumor-promoting activities, such as CXCL12, PTGS2, IL-6, and HGF upon ADSC-MMC-co-culture. In this context, a significant increase (up to 5,145-fold) in the expression of numerous tumor-associated proteins could be observed, e.g. several pro-angiogenic factors, such as VEGF, IL-8, and CCL2, as well as different matrix metalloproteinases, especially MMP-2. In conclusion, the current report clearly demonstrates that a bi-directional crosstalk between ADSCs and melanoma cells can enhance different malignant properties of melanoma cells in vitro.

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Fig. 1: Up-/downregulation of key genes in MMCs and ADSCs after co-culture
Fig. 2: Changes in migratory and invasive capacity of ADSCs and different melanoma cell lines under co-culture conditions
Fig. 3: Qualitative assessment of changes in migration and invasion of ADSCs and different melanoma cell lines
Fig. 4: Induction of angiogenesis

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Abbreviations

ADSCs:

Adipose tissue-derived stem cells

bFGF:

Basic fibroblast growth factor

CCL:

C-C motif-ligand

CD:

Cluster of differentiation

COX-2:

Cyclooxygenase-2

CXCL:

C-X-C motif ligand

ECM:

Extracellular matrix

EMT:

Epithelial-mesenchymal-transition

EMMPRIN:

Extracellular matrix metalloproteinase inducer

FCS:

Fetal calf serum

FN:

Fibronectin

HGF:

Hepatocyte growth factor

hMSCs:

Human mesenchymal stem/stroma cells

HUVEC:

Human umbilical vein endothelial cells

IL:

Interleukin

MCAM:

Melanoma cell adhesion molecule

MMCs:

Malignant melanoma cells

MMP:

Matrix metalloproteinase

PMA:

Phorbol 12-myristate 13-acetate

SD:

Standard deviation

PTGS2:

Prostaglandin-endoperoxide synthase 2

TW:

Transwell

VEGF:

Vascular endothelial growth factor.

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Acknowledgements

We would like to thank Claudia Ziegelmeier and Iris Kaiser for technical support with the multiplex analysis and Prof. Dr. Holger Sültmann (Division of Cancer Genome Research, NCT and German Cancer Research Center, Heidelberg, Germany) for providing access to the Bio-Plex 200 System.

Author information

Authors and Affiliations

  1. ETHIANUM - Clinic for Plastic, Aesthetic and Reconstructive Surgery, Spine, Orthopedic and Hand Surgery, Preventive Medicine, Voßstraße 6, 69115, Heidelberg, Germany

    Fabian Preisner, Uwe Leimer, Stefanie Sandmann, Guenter Germann & Eva Koellensperger

  2. Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University Hospital, Im Neuenheimer Feld 460, 60120, Heidelberg, Germany

    Inka Zoernig

Authors
  1. Fabian Preisner
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  2. Uwe Leimer
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  3. Stefanie Sandmann
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  4. Inka Zoernig
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  5. Guenter Germann
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  6. Eva Koellensperger
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Corresponding author

Correspondence to Eva Koellensperger.

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Preisner, F., Leimer, U., Sandmann, S. et al. Impact of Human Adipose Tissue-Derived Stem Cells on Malignant Melanoma Cells in An In Vitro Co-culture Model. Stem Cell Rev and Rep 14, 125–140 (2018). https://doi.org/10.1007/s12015-017-9772-y

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  • DOI: https://doi.org/10.1007/s12015-017-9772-y

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