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Cited by 262Extracellular vesicles in diseaseWnt/β-catenin signaling in development and cancerCancer Cells and Metastasis

WNT5A induces release of exosomes containing pro-angiogenic and immunosuppressive factors from malignant melanoma cells

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Ekström, Elin J, Bergenfelz, Caroline, von Bülow, Verena, Serifler, Filiz, Carlemalm, Eric, Jönsson, Göran, Andersson, Tommy, Leandersson, Karin·2014·Molecular Cancer
DOI 10.1186/1476-4598-13-88PMC PMC4022450
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Abstract

Background: Wnt proteins are important for developmental processes and certain diseases. WNT5A is a non-canonical Wnt protein that previously has been shown to play a role in the progression of malignant melanoma. High expression of WNT5A in melanoma tumors correlates to formation of distant metastasis and poor prognosis. This has partly been described by the findings that WNT5A expression in melanoma cell lines increases migration and invasion. Methods: Malignant melanoma cell lines were treated with rWNT5A or WNT5A siRNA, and mRNA versus protein levels of soluble mediators were measured using RT-PCR, cytokine bead array and ELISA. The induced signaling pathways were analyzed using inhibitors, Rho-GTPase pull down assays and western blot. Ultracentrifugation and electron microscopy was used to analyze microvesicles. Gene expression microarray data obtained from primary malignant melanomas was used to verify our data. Results: We show that WNT5A signaling induces a Ca 2+-dependent release of exosomes containing the immunomodulatory and pro-angiogenic proteins IL-6, VEGF and MMP2 in melanoma cells. The process was independent of the transcriptional machinery and depletion of WNT5A reduced the levels of the exosome-derived proteins. The WNT5A induced exosomal secretion was neither affected by Tetanus toxin nor Brefeldin A, but was blocked by the calcium chelator Bapta, inhibited by a dominant negative version of the small Rho-GTPase Cdc42 and was accompanied by cytoskeletal reorganization. Co-cultures of melanoma/endothelial cells showed that depletion of WNT5A in melanoma cells decreased endothelial cell branching, while stimulation of endothelial cells with isolated rWNT5A-induced melanoma exosomes increased endothelial cell branching in vitro. Finally, gene expression data analysis of primary malignant melanomas revealed a correlation between WNT5A expression and the angiogenesis marker ESAM. Conclusions: These data indicate that WNT5A has a broader function on tumor progression and metastatic spread than previously known; by inducing exosome-release of immunomodulatory and pro-angiogenic factors that enhance the immunosuppressive and angiogenic capacity of the tumors thus rendering them more aggressive and more prone to metastasize.

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  • Melanoma cells promote growth and invasion through the secretion of protumorigenic factors.

    “Given the ability of melanoma cells to promote growth and invasion through the secretion of protumorigenic factors (11–13), it is plausible that beyond cancer cell–intrinsic mechanisms, phenotype plasticity and ferroptosis vulnerability of drug-resistant clones may involve autocrine or paracrine circuits.”

    From Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis (2024) · cites this paper as [13]

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Cited by

Sorted by citations

Authors
Ekström, E. J., Bergenfelz, C., von Bülow, V., Serifler, F., Carlemalm, E., Jönsson, G., Andersson, T., & Leandersson, K.
Affiliations
Lund University (SE)
Corresponding author
Leandersson, Karin
ORCID
Venue
Molecular Cancer
Publisher
Springer Science and Business Media LLC
Published
2014-04-26
Volume
13
Issue
1
Pages
88-88
ISSN
1476-4598 (ISSN-L)
DOI
10.1186/1476-4598-13-88
PMC
PMC4022450
OpenAlex
W2112395933
Cited by
262
References
0
Citations by year
2026: 2 · 2025: 17 · 2024: 14 · 2023: 20 · 2022: 25 · 2021: 33 · 2020: 29 · 2019: 22 · 2018: 25 · 2017: 18 · 2016: 30 · 2015: 21 · 2014: 6
FWCI
10.26
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Molecular Cancer (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Lund University Publications (Lund University) (submittedVersion, other-oa)
Funders
  • Swedish Cancer Foundation
  • Medical Research Council
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
Wnt5a, melanoma, exosomes, exosome secretion, non-canonical Wnt signaling, angiogenesis, immunosuppression, interleukin-6, vascular endothelial growth factor, MMP-2, calcium signaling, Cdc42, Rho GTPases, cytoskeletal remodeling, metastasis, ESAM, tumor microenvironment
MeSH terms
Wnt-5a Protein, Calcium, Cell Movement, Egtazic Acid, Humans, Melanoma, Neovascularization, Pathologic, Proto-Oncogene Proteins, Skin Neoplasms, Tetanus Toxin, Signal Transduction, Cell Adhesion Molecules, Interleukin-6, Gene Expression Regulation, Neoplastic, Coculture Techniques, Brefeldin A, cdc42 GTP-Binding Protein, Matrix Metalloproteinase 2, Vascular Endothelial Growth Factor A, Endothelial Cells, Cell Line, Tumor, Cell Proliferation, Wnt Proteins, Exosomes

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