Exosomes produced by melanoma cells significantly influence the biological properties of normal and cancer-associated fibroblasts

Abstract

The incidence of cutaneous malignant melanoma is increasing worldwide. While the treatment of initial stages of the disease is simple, the advanced disease frequently remains fatal despite novel therapeutic options . This requires identification of novel therapeutic targets in melanoma. Similarly to other types of tumours, the cancer microenvironment plays a prominent role and determines the biological properties of melanoma. Importantly, melanoma cell-produced exosomes represent an important tool of intercellular communication within this cancer ecosystem. We have focused on potential differences in the activity of exosomes produced by melanoma cells towards melanoma-associated fibroblasts and normal dermal fibroblasts. Cancer-associated fibroblasts were activated by the melanoma cell-produced exosomes significantly more than their normal counterparts, as assessed by increased transcription of genes for inflammation-supporting cytokines and chemokines, namely IL-6 or IL-8. We have observed that the response is dependent on the duration of the stimulus via exosomes and also on the quantity of exosomes. Our study demonstrates that melanoma-produced exosomes significantly stimulate the tumour-promoting proinflammatory activity of cancer-associated fibroblasts. This may represent a potential new target of oncologic therapy .

Cancer-Associated Fibroblasts Influence the Biological Properties of Malignant Tumours via Paracrine Secretion and Exosome Production

“…This finding reflects well the secretory senescent phenotype of the CAFs observed earlier [131,132]. This cellular phenotype is associated with the upregulation of miR-335 Melanoma-derived CaExos negatively influence the adhesion and proliferation of both the normal dermal fibroblasts and melanoma CAFs in a dose-dependent manner [130]. This finding reflects well the secretory senescent phenotype of the CAFs observed earlier [131,132].…”

“…Indeed, CAFs can bind and internalise exosomes (Figure 4) and be subject to regulation by cancer cells. Melanoma-derived CaExos negatively influence the adhesion and proliferation of both the normal dermal fibroblasts and melanoma CAFs in a dose-dependent manner [130]. This finding reflects well the secretory senescent phenotype of the CAFs observed earlier [131,132].…”

“…This may be understood to be a model of the invasive front mentioned earlier. Further, CaExos (melanoma) also stimulated the migration of melanoma cells from heterogeneous spheroids prepared from the melanoma cells and melanoma-isolated CAFs (Figure 5) in collagen gels [130]. CAFs from cutaneous basal cell carcinoma were treated by commercially available GFPtagged exosomes for 12 h. Cells were consequently fixed by paraformaldehyde, permeabilised, and counterstained using phalloidin-TRITC (to show actin in the cytoplasm) and DAPI (to show DNA in the nuclei).…”

In focus in HCB

“…In their present work, Strnadová et al (2022) investigated the effect of melanoma cell-derived exosomes on cultured normal human dermal fibroblasts (HDF) and on melanomaassociated fibroblasts (mCAF) alone and in combination with melanoma cells. Among three melanoma cell lines (A2058, BLM, and G361) analyzed, the G361 cell line, established from a primary malignant melanoma, provided a rich source of exosomes.…”

“…1 Normalized invasion index of melanoma cells grown as spheroids with either melanoma-associated fibroblasts (mCAF) or normal human dermal fibroblasts (HDF). From Strnadová et al (2022) In their transcriptomic analysis, the authors detected a significant, albeit different influence of G361 exosomes on fibroblasts. For instance, although genes for cytokines and chemokines were upregulated in mCAF, they were unchanged or downregulated in HDF.…”