TY - JOUR
T1 - Extracellular Vesicles Released by Tumor Endothelial Cells Spread Immunosuppressive and Transforming Signals Through Various Recipient Cells
AU - Lopatina, Tatiana
AU - Favaro, Enrica
AU - Danilova, Ludmila
AU - Fertig, Elana J.
AU - Favorov, Alexander V.
AU - Kagohara, Luciane T.
AU - Martone, Tiziana
AU - Bussolati, Benedetta
AU - Romagnoli, Renato
AU - Albera, Roberto
AU - Pecorari, Giancarlo
AU - Brizzi, Maria Felice
AU - Camussi, Giovanni
AU - Gaykalova, Daria A.
N1 - Funding Information:
Funding. This work was supported by NIH R01DE027809 and JHU Catalyst Award (DG). Additional funding was provided by P30 CA006973 (LD, AF, and EJF), R50 CA243627 (LD), R01 CA177669 (EJF). This work was also supported by Associazione Italiana per la Ricerca sul Cancro (AIRC) project IG 12890 (GC), project IG 2015.17630 (MB), and project IG2015 16973 (BB) and by Russian Basic Research Foundation grant RBRF 17-00-00208 (LD and AF). This manuscript has been released as a pre-print at ISEV2019 Abstract Book (Lopatina et al., 2019a).
Publisher Copyright:
© Copyright © 2020 Lopatina, Favaro, Danilova, Fertig, Favorov, Kagohara, Martone, Bussolati, Romagnoli, Albera, Pecorari, Brizzi, Camussi and Gaykalova.
PY - 2020/9/9
Y1 - 2020/9/9
N2 - 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.
AB - 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.
KW - T regulatory (T reg) cells
KW - extracellular vesicles
KW - head and neck cancer
KW - tumor endothelial cells
KW - tumor immune editing
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U2 - 10.3389/fcell.2020.00698
DO - 10.3389/fcell.2020.00698
M3 - Article
C2 - 33015029
AN - SCOPUS:85091430542
SN - 2296-634X
VL - 8
JO - Frontiers in Cell and Developmental Biology
JF - Frontiers in Cell and Developmental Biology
M1 - 698
ER -