Chronic stress promotes gastric cancer progression and metastasis: an essential role for ADRB2

Abstract

An increasing number of studies indicate that adrenergic signalling plays a fundamental role in chronic stress-induced tumour progression and metastasis. However, its function in gastric cancer (GC) and its potential mechanisms remain unknown. The expression levels of β-adrenergic receptor (ADRB) in GC cell lines were examined by using real-time polymerase chain reaction (RT-PCR) and western blotting. The effects of β2 adrenergic receptor (ADRB2) activation and blockade were investigated in vitro in GC cells by using proliferation, migration, invasion, cell cycle and apoptosis assays. Chronic restraint stress (CRS) increased the plasma levels of catecholamines and cortisol and also induced progression and metastasis of GC in vivo. Furthermore, immunohistochemical staining and a TUNEL assay were employed to observe the regulation of cell viability in vivo. The expression levels of ADRB2 in 100 human GC samples were measured by RT-PCR and immunohistochemistry. The stress hormones epinephrine and norepinephrine significantly accelerated GC cell proliferation, invasion and viability in culture, as well as tumour growth in vivo. These effects were reversed by the ADRB antagonists propranolol and ICI118,551 (an ADRB2-specific antagonist). Moreover, the selective ADRB1 antagonist atenolol had almost no effect on tumour cell proliferation and invasion in vitro and in vivo. ADRB2 antagonists suppressed proliferation, invasion and metastasis by inhibiting the ERK1/2-JNK-MAPK pathway and transcription factors, such as NF-κB, AP-1, CREB and STAT3. Analysis of xenograft models using GC cells revealed that ADRB2 antagonists significantly inhibited tumour growth and metastasis, and chronic stress antagonized these inhibitory effects. In addition, chronic stress increased the expression of VEGF, MMP-2, MMP-7 and MMP-9 in transplanted tumour tissue, and catecholamine hormones enhanced the expression of metastasis-related proteins. The expression of ADRB2 was upregulated in tumour tissues and positively correlated with tumour size, histological grade, lymph node metastasis and clinical stage in human GC samples. Stress hormone-induced activation of the ADRB2 signalling pathway plays a crucial role in GC progression and metastasis. These findings indicate that ADRB2 signalling regulates GC progression and suggest β2 blockade as a novel strategy to complement existing therapies for GC.

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“…Studies have provided evidence indicating ligand activation of β adrenergic receptor modulated signaling may either promote or blunt proliferation of malignantly transformed cells in glioma models [4,[38][39][40][41][42][43][44] and extra-neuraxial carcinoma [45][46][47][48][49]. Specifically, ligand activation of β adrenergic receptors potently amplifies cellular proliferation in lung [7], gastric [50], hepatocellular [51], pancreatic [52], colorectal [53], breast [54,55], ovarian [56,57], and prostatic [49] carcinoma models in vitro. Paradoxically, pharmacological antagonism of β adrenergic receptors also potently attenuates cellular proliferation in hemangioblastoma [58] and hepatic [55], pancreatic [59], gastric [50], colorectal [46], breast [54,55], ovarian, and prostatic [60] carcinoma models in vitro.…”

“…Specifically, ligand activation of β adrenergic receptors potently amplifies cellular proliferation in lung [7], gastric [50], hepatocellular [51], pancreatic [52], colorectal [53], breast [54,55], ovarian [56,57], and prostatic [49] carcinoma models in vitro. Paradoxically, pharmacological antagonism of β adrenergic receptors also potently attenuates cellular proliferation in hemangioblastoma [58] and hepatic [55], pancreatic [59], gastric [50], colorectal [46], breast [54,55], ovarian, and prostatic [60] carcinoma models in vitro. β antagonists reduce cellular proliferation and migration in neuroblastoma cell lines [8], enhance therapeutic concentrations of co-administered medications [8], and reduce expression of P-glycoprotein inhibitors [61].…”

Chronic Stress Promotes Cancer Development

“…The relationship between chronic stress and cancers has aroused increasingly widespread interest and concern in the medical community. Many scholars have performed research on the relationships between stress and cancers such as prostate (8)(9)(10), breast (8)(9)(10)(11)(12), gastric (13,14), lung (15,16), and skin cancer (17,18), and have found evidence indicating that chronic stress can induce tumorigenesis and promote cancer development ( Table 1).…”

Gastric Cancer Heterogeneity and Clinical Outcomes

“…Zhang et al described ADRB2 signaling as essential in GC and is likely related to stress-induced tumor induction. 58 They suggest treating with antagonists of ARDB2 likely will provide survival benefit. This may be important to note and be beneficial for nonintestinal like GCs because there is a clear trend of significant downregulation of this gene (−2.631 fold difference).…”