Wnt5a Inhibits Human Monocyte‐Derived Myeloid Dendritic Cell Generation

Bergenfelz, Caroline; Janols, Helena; Wullt, Marlene; Jirström, Karin; Bredberg, Anders; Leandersson, Karin

doi:10.1111/sji.12075

Cited by 23 publications

(22 citation statements)

References 51 publications

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“…rWNT5A also induced IL-6 secretion over a longer time period as measured by Elisa at 3 h, 6 h, 12 h, 24 h and 48 h (Figure 1C). We have previously shown that WNT5A induces IL-10 [27] and IL-6 [28] in human monocytes. In Mewo cells however, IL-10 was not even expressed at the mRNA level (data not shown).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2014

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BackgroundWnt 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.MethodsMalignant 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.ResultsWe show that WNT5A signaling induces a Ca2+-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.ConclusionsThese 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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Section: Resultsmentioning

confidence: 99%

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

et al. 2014

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“…Mesenchymal glioblastomas have a higher probability of elevated expression of SPP1 than do other subtypes of glioblastoma, whereas classical glioblastomas are less likely to express SPP1 in glioblastoma-infiltrating innate immune cells. The role of WNT5A in modulation of the glioblastoma microenvironment has yet to be explored, but researchers have shown it to mediate monocyte accumulation in patients with cancer (58) and induce macrophage-related breast cancer cell invasion (59). Finally, several of the upregulated genes in CD14 + cells are directly implicated in clinical characteristics such as the extent of edema on magnetic resonance images (60).…”

Section: Discussionmentioning

confidence: 99%

Glioblastoma-infiltrated innate immune cells resemble M0 macrophage phenotype

et al. 2016

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Glioblastomas are highly infiltrated by diverse immune cells, including microglia, macrophages, and myeloid-derived suppressor cells (MDSCs). Understanding the mechanisms by which glioblastoma-associated myeloid cells (GAMs) undergo metamorphosis into tumor-supportive cells, characterizing the heterogeneity of immune cell phenotypes within glioblastoma subtypes, and discovering new targets can help the design of new efficient immunotherapies. In this study, we performed a comprehensive battery of immune phenotyping, whole-genome microarray analysis, and microRNA expression profiling of GAMs with matched blood monocytes, healthy donor monocytes, normal brain microglia, nonpolarized M0 macrophages, and polarized M1, M2a, M2c macrophages. Glioblastoma patients had an elevated number of monocytes relative to healthy donors. Among CD11b+ cells, microglia and MDSCs constituted a higher percentage of GAMs than did macrophages. GAM profiling using flow cytometry studies revealed a continuum between the M1- and M2-like phenotype. Contrary to current dogma, GAMs exhibited distinct immunological functions, with the former aligned close to nonpolarized M0 macrophages.

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“…However, neither WNT5A protein nor WNT5A mRNA expression were affected in the WM852 and the A2058 cell lines. In this context, it deserves to be mentioned that a reverse mechanism has been reported, in that WNT5A can increase the expression of IL‐6 both in vitro in monocytes (Bergenfelz et al., 2013) and in vivo in the spinal cord (Li et al., 2013). These findings might explain the observation by Dissanayake et al.…”

Section: Discussionmentioning

confidence: 99%

Interleukin‐6 drives melanoma cell motility through p38α‐MAPK‐dependent up‐regulation of WNT5A expression

et al. 2014

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Extensive research has demonstrated a tumor‐promoting role of increased WNT5A expression in malignant melanoma. However, very little light has been shed upon how WNT5A expression is up‐regulated in melanoma. A potential regulator of WNT5A expression is the pro‐inflammatory cytokine Interleukin (IL)‐6, which shares the ability of WNT5A to increase melanoma cell invasion. Here, we investigate whether IL‐6 can promote melanoma cell motility through an increased expression of WNT5A. We clearly demonstrate that the WNT5A‐antagonistic peptide Box5 could inhibit IL‐6‐induced melanoma cell migration and invasion. Furthermore, IL‐6 stimulation of the human melanoma cell lines HTB63 and A375 increased the expression of WNT5A in a dose‐dependent manner. To identify the signaling mechanism responsible for this up‐regulation, we explored the involvement of the three main signals induced by IL‐6; STAT3, Akt and ERK 1/2. Of these, only STAT3 was activated by IL‐6 in the melanoma cell lines tested. However, the STAT3 inhibitor S3I‐201 failed to inhibit IL‐6‐induced WNT5A up‐regulation in HTB63 and A375 cells. Nor did STAT3 siRNA silencing affect the expression of WNT5A. In search of an alternative signaling mechanism, we detected IL‐6‐induced activation of p38‐MAPK in HTB63 and A375 cells. The p38‐MAPK inhibitor SB203580 abolished the IL‐6‐induced WNT5A up‐regulation and blocked IL‐6‐induced melanoma cell invasion. The latter effect could be rescued by the addition of recombinant WNT5A. Notably, immunoprecipitation analysis revealed that only the p38α‐MAPK isoform was activated by IL‐6, and subsequent siRNA silencing of p38α‐MAPK abolished the IL‐6‐induced up‐regulation of WNT5A. Taken together, we demonstrate a novel link between the two melanoma pro‐metastatic agents IL‐6 and WNT5A explaining how IL‐6 can increase melanoma cell invasion and thus promote the metastatic process. This finding provides a basis for future therapeutic intervention of melanoma progression.

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Wnt5a Inhibits Human Monocyte‐Derived Myeloid Dendritic Cell Generation

Cited by 23 publications

References 51 publications

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

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

Glioblastoma-infiltrated innate immune cells resemble M0 macrophage phenotype

Interleukin‐6 drives melanoma cell motility through p38α‐MAPK‐dependent up‐regulation of WNT5A expression

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