Abstract
It is known that chronic stress modulates multiple processes in a complex microenvironment, such as angiogenesis and immune function. However, the role of chronic stress inducing tumor angiogenesis and how it contributes to tumor progression are not quite clear. The following study assess psychological state from numerous ambulatory cancer cases (n=332), and chronic stress-related hormone levels were further measured. Here, we show that chronic stress not only causes behavioral changes in human, most importantly attributed to an elevated level of stress-related hormones. To address this, isoprenaline, the agonist of β2-adrenergic receptor (β2-AR), was utilized for simulating chronic stress and demonstrating the mechanism of stress in tumor angiogenesis at molecular level both in vivo and in vitro. As suggested by this study, isoprenaline promote VEGF autocrine of HUVECs, which can induce plexinA1 and VEGFR2 expression. Moreover, we show that isoprenaline promoted the expression of p-JAK2 and p-STAT3 in vitro. The results reveal that, isoprenaline enhances the autocrine of VEGF in HUVECs and up-regulating plexinA1 and VEGFR2 levels, thus activating the phosphorylation of JAK2-STAT3 pathway, the two essential parts during angiogenesis. The present work indicates that, the mechanism of chronic stress in enhancing angiogenesis is probably achieved through activating the plexinA1/VEGFR2-JAK2-STAT3 signal transduction pathway within HUVECs, and this is probably a candidate target for developing a strategy against angiogenesis in cancer.
Highlights
After being diagnosed as a malignant tumor, most clinical tumor patients will have a variety of psychological stress such as shock, denial, anxiety and fear
Our previous study detected the microvessel density within gastric cancer and reported the positive correlation between plexinA1 and angiogenesis [16]. plexinA1 and VEGF receptor2 (VEGFR2) are co-localized within vascular endothelial cells (VECs) of gastric cancer [17]. we examined the relationship between plexinA1 and VEGFR2 in tumour angiogenesis mediated by chronic stress
The b2-adrenergic receptor (b2-AR) expression were obtained from western-blotting analysis. (Figure 3F) Further, our findings revealed that VEGFR2 and plexinA1 upregulated by ISO stimulation, whereas ICI treatment reduced mRNA (Figure 3E) and proteins (Figure 3F) expression of VEGFR2 and plexinA1
Summary
After being diagnosed as a malignant tumor, most clinical tumor patients will have a variety of psychological stress such as shock, denial, anxiety and fear. Surgery and chemoradiotherapy process caused by pain, nausea, vomiting, infection and other side effects will promote the patient disappointment, anger and depression psychological problems [1, 2]. As indicated in some works, catecholamine’s can activate the b2-adrenergic receptors (b2-AR), mediating tumour cells and tumour microenvironment [5, 6]. Little is known about the exact mechanism of angiogenesis induced by stress in the context of tumour. This work mainly aimed to explore the precise mechanism by which isoprenaline, the b2-AR agonist, participated in the tumour angiogenesis
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