Abstract
Tumor-derived exosomes containing the tetraspanin Tspan8 can efficiently induce angiogenesis in tumors and tumor-free tissues. However, little information exists on exosome-endothelial cell (EC) interactions or the proangiogenic role of tetraspanins, which are a constitutive component of exosomes. In this study, we used a rat adenocarcinoma model (AS-Tspan8) to explore the effects of exosomal Tspan8 on angiogenesis. Tspan8 contributed to a selective recruitment of proteins and mRNA into exosomes, including CD106 and CD49d, which were implicated in exosome-EC binding and EC internalization. We found that EC internalized Tspan8-CD49d complex-containing exosomes. Exosome uptake induced vascular endothelial growth factor (VEGF)-independent regulation of several angiogenesis-related genes, including von Willebrand factor, Tspan8, chemokines CXCL5 and MIF, chemokine receptor CCR1, and, together with VEGF, VEGF receptor 2. EC uptake of Tspan8-CD49d complex-containing exosomes was accompanied by enhanced EC proliferation, migration, sprouting, and maturation of EC progenitors. Unraveling these new pathways of exosome-initiated EC regulation could provide new options for therapeutic interference with tumor-induced angiogenesis.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adenocarcinoma / genetics
-
Adenocarcinoma / metabolism
-
Adenocarcinoma / pathology
-
Animals
-
Antigens, Neoplasm / genetics
-
Antigens, Neoplasm / metabolism
-
Antigens, Neoplasm / physiology*
-
Antigens, Surface / genetics
-
Antigens, Surface / metabolism
-
Antigens, Surface / physiology
-
Cell Differentiation / drug effects
-
Cell Differentiation / genetics
-
Cell Membrane / metabolism
-
Cell Proliferation / drug effects
-
Cells, Cultured
-
Endothelial Cells / drug effects
-
Endothelial Cells / metabolism
-
Endothelial Cells / pathology
-
Endothelial Cells / physiology*
-
Exosomes / metabolism
-
Exosomes / pathology
-
Exosomes / physiology*
-
Gene Expression Regulation, Neoplastic / drug effects
-
Lung Neoplasms / genetics
-
Lung Neoplasms / metabolism
-
Lung Neoplasms / pathology
-
Membrane Glycoproteins / antagonists & inhibitors
-
Membrane Glycoproteins / genetics
-
Membrane Glycoproteins / metabolism
-
Membrane Glycoproteins / physiology*
-
Neoplasm Proteins / antagonists & inhibitors
-
Neoplasm Proteins / genetics
-
Neoplasm Proteins / metabolism
-
Neoplasm Proteins / physiology*
-
Neovascularization, Pathologic / genetics
-
Neovascularization, Pathologic / metabolism
-
Neovascularization, Pathologic / pathology
-
RNA, Small Interfering / pharmacology
-
Rats
-
Signal Transduction / drug effects
-
Signal Transduction / genetics
-
Tetraspanins
Substances
-
Antigens, Neoplasm
-
Antigens, Surface
-
Membrane Glycoproteins
-
Neoplasm Proteins
-
RNA, Small Interfering
-
Tetraspanins
-
Tspan8 protein, rat