Abstract
BackgroundThe role of stress signals in regulating gastric cancer initiation and progression is not quite clear. It is known that stress signals modulate multiple processes such as immune function, cell migration and angiogenesis. However, few studies have investigated the mechanisms of how stress signals contribute to gastric cancer angiogenesis.MethodsHere, we used β2-adrenergic receptor (β2-AR) agonist isoprenaline to imitate a stress signal and demonstrated the molecular mechanism underlying stress’s influence on tumor angiogenesis.ResultsWe found that isoprenaline stimulated vascular endothelial growth factor (VEGF) secretion in gastric cancer cells and plexin-A1 expression was induced by human recombinant VEGF165 in both gastric cancer cells and vascular endothelial cells. Furthermore, interfere with plexin-A1 expression in gastric cancer cells influence HUVEC tube formation, migration and tumor growth in vivo.ConclusionsThese findings suggest that isoprenaline stimulate VGEF secretion and subsequently up-regulate the expression of plexin-A1 and VEGFR2 in gastric cancer cells, which form a positive impetus to promote tumor angiogenesis. This study reveals a novel molecular mechanism that a stress signal like isoprenaline may enhance angiogenesis via activating plexin-A1/VEGFR2 signaling pathway in gastric cancer, which may be a potential target in development of an anti-angiogenic therapy for gastric cancer.
Highlights
The role of stress signals in regulating gastric cancer initiation and progression is not quite clear
A P-value
Plexin-A1 and VEGFR2 signals appeared to localize simultaneously in the tumor-associated vascular endothelial cells and tumor cells, but not in the normal gastric tissues (Figs. 2a-d and 3). These findings indicated plexinA1 and VEGFR2 may play a critical role in tumor angiogenesis
Summary
The role of stress signals in regulating gastric cancer initiation and progression is not quite clear. Few studies have investigated the mechanisms of how stress signals contribute to gastric cancer angiogenesis. The fact that targeting VEGF family receptors closely related to inhibition of VEGF-mediated signaling, proliferation and migration of endothelial cells [6] and anti-tumor activity in animal models, has been proven [7]. Targeting VEGF receptor (VEGFR2) has been tested in the patients with advanced gastric cancer in a Phase III study [8, 9]. This second-line therapy has not consistently translated into a survival advantage over standard treatment in randomized clinical trials.
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