Extracellular vesicles derived from cancer‐associated fibroblasts induce the migration and invasion of oral squamous cell carcinoma

Abstract

As one of the most abundant constituents of the tumour microenvironment (TME), cancer-associated fibroblasts (CAF) display critical roles during tumour progression and metastasis. Multiple classes of molecules including growth factors, cytokines, proteases and extracellular matrix proteins, are produced by CAF to act as mediators of the stroma-tumour interactions. One of the main channels for this communication is associated with extracellular vesicles (EV), which are secreted particles loaded with protein and genetic information. In this study, we evaluated the effects of EV derived from CAF primary human cell lines (n = 5) on proliferation, survival, migration, and invasion of oral squamous cell carcinoma (OSCC) cells. As controls, EV from human primary-established normal oral fibroblasts (NOF, n = 5) were used. Our in vitro assays showed that CAF-EV significantly induces migration and invasion of OSCC cells and promote a disseminated pattern of HSC-3 cell invasion in the 3D organotypic assay. Furthermore, gene expression analysis of EV-treated cancer cells revealed changes in the pathways associated with tumour metabolism and up-regulation of tumour invasion genes. Our findings suggest a significant role of CAF-EV in promoting the migration and invasion of OSCC cells, which are related to the activation of cancer-related pathways.

Extracellular Vesicles in Oral Squamous Cell Carcinoma and Oral Potentially Malignant Disorders: A Systematic Review

“…Microarray was performed on total RNA isolated from HSC3 cell line treated with CAF-EV or NF-EV, identifying thirty-two differentially expressed (FC ≥ 1.3) genes. These findings support CAF-EV mediated influence on OSCC behaviour and gene expression which may be those OSCCs that already possess higher invasive and metastatic potential [37].…”

“…Effects of EVs derived from 5 primary CAF lines and 5 primary NF lines were studied on 4 TOSCC cell lines: HSC3 and SAS (higher invasive and metastatic potential) and the less aggressive SSC-15 and SSC-25 cell lines [37]. The invasive potential of HSC-3, SAS and SCC-15, but not SCC-25, was significantly increased (p < 0.05) by co-culture with individual CAF-EVs compared to NF-EVs and controls.…”

Extracellular Vesicles and Cancer: A Focus on Metabolism, Cytokines, and Immunity

“…Luga and colleagues showed that CAFs-secreted sEVs are potent regulators of the Wnt-planar cell polarity pathway in breast cancer cells favoring cancer metastasis [44] and Santi demonstrated that CAFs transfer lipids and proteins to cancer cells through EVs supporting tumor growth [45]. Recently, Dourado and colleagues suggest that EVs released by CAFs induce migration and invasion of oral squamous cell carcinoma cells [46]. Moreover, Qin X and colleagues provided evidence that EVs contain miR-196a, which confers cis-platin resistance in head and neck cancer through targeting CDKN1B and ING5 [47].…”

Fibroblasts modulate the tumor cell motility and their mTOR/S6K1 phosphorylation status in vitro

“…Moreover, the stromal cells are able to increase significantly the viability of cancer cells and their resistance to chemotherapy and radiotherapy. Therefore, the mutual interaction of stromal and tumor cells has been recently intensively investigated [4][5][6][7]. In particular, the effect of cancer-associated fibroblasts (CAFs) on the behavior of tumor cells has been investigated in different tumor types [8,9].…”