Cell surface tetraspanin Tspan8 contributes to molecular pathways of exosome-induced endothelial cell activation.
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.
Nazarenko
Irina
I
Department of Tumor Cell Biology, University Hospital of Surgery, D-69120 Heidelberg, Germany.
Rana
Sanyukta
S
Baumann
Alexandra
A
McAlear
Jessica
J
Hellwig
Andrea
A
Trendelenburg
Michael
M
Lochnit
Günter
G
Preissner
Klaus T
KT
Zöller
Margot
M
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D055354:Exosomes / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D059470:Tetraspanins
D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D059470:Tetraspanins; C111874:Tspan8 protein, rat