Abstract
Head and neck squamous cell carcinoma (HNSCC) has a high recurrence and metastatic rate with an unknown mechanism of cancer spread. Tumor inflammation is the most critical processes of cancer onset, growth, and metastasis. We hypothesize that the release of extracellular vesicles (EVs) by tumor endothelial cells (TECs) induce reprogramming of immune cells as well as stromal cells to create an immunosuppressive microenvironment that favor tumor spread. We call this mechanism as non-metastatic contagious carcinogenesis. Extracellular vesicles were collected from primary HNSCC-derived endothelial cells (TEC-EV) and were used for stimulation of peripheral blood mononuclear cells (PBMCs) and primary adipose mesenchymal stem cells (ASCs). Regulation of ASC gene expression was investigated by RNA sequencing and protein array. PBMC, stimulated with TEC-EV, were analyzed by enzyme-linked immunosorbent assay and fluorescence-activated cell sorting. We validated in vitro the effects of TEC-EV on ASCs or PBMC by measuring invasion, adhesion, and proliferation. We found and confirmed that TEC-EV were able to change ASC inflammatory gene expression signature within 24–48 h. TEC-EV were also able to enhance the secretion of TGF-β1 and IL-10 by PBMC and to increase T regulatory cell (Treg) expansion. TEC-EV carry specific proteins and RNAs that are responsible for Treg differentiation and immune suppression. ASCs and PBMC, treated with TEC-EV, enhanced proliferation, adhesion of tumor cells, and their invasion. These data indicate that TEC-EV exhibit a mechanism of non-metastatic contagious carcinogenesis that regulates tumor microenvironment and reprograms immune cells to sustain tumor growth and progression.
Highlights
Tumor angiogenesis, the formation of new blood vessels within a tumor, is one of the crucial steps of tumor growth and progression (Folkman, 1985)
tumor endothelial cells (TECs)-extracellular vesicles (EVs) were analyzed by ribonucleic acid (RNA) sequencing, protein array, fluorescence-activated cell sorting (FACS), and enzyme-linked immunosorbent assay (ELISA) and were used for stimulation of two types of recipient cells I (ASCs and peripheral blood mononuclear cell (PBMC))
PBMC stimulated with TEC-EV (PBMCind) were analyzed by ELISA and FACS to demonstrate activation and differentiation
Summary
The formation of new blood vessels within a tumor, is one of the crucial steps of tumor growth and progression (Folkman, 1985). TECs are the cells lining the tumor-associated blood vessels (Dudley, 2012). Recent data suggest that TEC play a critical role in tumor growth and metastasis (Osawa et al, 2013; Yadav et al, 2015), and show characteristics of cancer stem cells (Dudley et al, 2008). TEC could regulate tumor microenvironment since they have direct contact with blood cells and vessel stromal cells. This regulation is mediated via production of increased levels of growth factors and cytokines, as well as via release of EV. EV are membrane vesicles containing a specific set of proteins, lipids, and nucleic acids, which could incorporate into recipient cells via cell surface receptors and regulate their gene expression (Quesenberry et al, 2015)
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