Systemic induction of the angiogenesis switch by the tetraspanin D6.1A/CO-029.
Expression of the tetraspanin CO-029 is associated with poor prognosis in patients with gastrointestinal cancer. In a pancreatic tumor line, overexpression of the rat homologue, D6.1A, induces lethally disseminated intravascular coagulation, suggesting D6.1A engagement in angiogenesis. D6.1A-overexpressing tumor cells induce the greatest amount of angiogenesis in vivo, and tumor cells as well as exosomes derived thereof strikingly increase endothelial cell branching in vitro. Tumor cell-derived D6.1A stimulates angiogenic factor transcription, which includes increased matrix metalloproteinase and urokinase-type plasminogen activator secretion, pronounced vascular endothelial growth factor expression in fibroblasts, vascular endothelial growth factor receptor expression, and strong D6.1A up-regulation in sprouting endothelium. Thus, D6.1A initiates an angiogenic loop that, probably due to the abundance of D6.1A in tumor-derived exosomes, reaches organs distant from the tumor. Most importantly, because of the strong D6.1A up-regulation on sprouting capillaries, angiogenesis could be completely inhibited by a D6.1A-specific antibody, irrespective of whether or not the tumor expresses D6.1A. Tetraspanins have been suggested to be involved in morphogenesis. This is the first report that a tetraspanin, CO-029/D6.1A, promotes tumor growth by its capacity to induce systemic angiogenesis that can effectively, and with high selectivity for sprouting endothelium, be blocked by a D6.1A-specific antibody.
Gesierich
Sabine
S
Department of Tumor Progression and Immune Defence, German Cancer Research Centre, Heidelberg, Germany.
Berezovskiy
Igor
I
Ryschich
Eduard
E
Zöller
Margot
M
D000230:Adenocarcinoma / Q000098:blood supply* / Q000378:metabolism; D000818:Animals; D017364:Collagenases / Q000096:biosynthesis / Q000235:genetics; D004730:Endothelium, Vascular / Q000378:metabolism; D053509:Matrix Metalloproteinase 13; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000502:physiology*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D059470:Tetraspanins; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D059470:Tetraspanins; C111874:Tspan8 protein, rat; D042461:Vascular Endothelial Growth Factor A; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507083:Mmp13 protein, rat