Effect of Chronic Restraint Stress on Human Colorectal Carcinoma Growth in Mice

Abstract

Stress alters immunological and neuroendocrinological functions. An increasing number of studies indicate that chronic stress can accelerate tumor growth, but its role in colorectal carcinoma (CRC) progression is not well understood. The aim of this study is to investigate the effects of chronic restraint stress (CRS) on CRC cell growth in nude mice and the possible underlying mechanisms. In this study, we showed that CRS increased the levels of plasma catecholamines including epinephrine (E) and norepinephrine (NE), and stimulated the growth of CRC cell-derived tumors in vivo. Treatment with the adrenoceptor (AR) antagonists phentolamine (PHE, α-AR antagonist) and propranolol (PRO, β-AR antagonist) significantly inhibited the CRS-enhanced CRC cell growth in nude mice. In addition, the stress hormones E and NE remarkably enhanced CRC cell proliferation and viability in culture, as well as tumor growth in vivo. These effects were antagonized by the AR antagonists PHE and PRO, indicating that the stress hormone-induced CRC cell proliferation is AR dependent. We also observed that the β-AR antagonists atenolol (ATE, β1- AR antagonist) and ICI 118,551 (ICI, β2- AR antagonist) inhibited tumor cell proliferation and decreased the stress hormone-induced phosphorylation of extracellular signal-regulated kinases-1/2 (ERK1/2) in vitro and in vivo. The ERK1/2 inhibitor U0126 also blocked the function of the stress hormone, suggesting the involvement of ERK1/2 in the tumor-promoting effect of CRS. We conclude that CRS promotes CRC xenograft tumor growth in nude mice by stimulating CRC cell proliferation through the AR signaling-dependent activation of ERK1/2.

Catecholamines Increase in Vitro Proliferation of Murine B16F10 Melanoma Cells

“…These results are confirmed by another study that showed a 35% increase of HT29 cell proliferation induced by epinephrine treatment at the concentration of 10 µM (67). Other research on HT29, SW116 and LS174T colorectal carcinoma cell lines showed that the stress hormones epinephrine and norepinephrine at concentrations of 0.1-10 µM markedly increase the cell proliferation with no significant effect induced by corticosterone (53).…”

“…Basal plasma levels may range between 0.5 nM and 15 nM (50-52), up to 200 nM (53) for epinephrine and from 2 to 20 nM (50)(51)(52) or even in some conditions over 4 µM (53) for norepinephrine. Stress increases these levels to 10 -25 nM (50-52) or even 300 nM (53) for epinephrine and to 25-60 nM (50-52) going in some conditions over 1 µM (53) for norepinephrine. Moreover, recent results have shown that plasma levels of norepinephrine are significantly higher in mice with B16-F10 melanoma metastases than in non-tumor controls (48).…”

Sympathetic nervous system regulation of the tumour microenvironment

“…However, the epidemiological literature is also inconsistent, and some studies fail to find any evidence of a protective effect (likely due to methodological variations considered below). In experimental animal models of human cancer, β-antagonists can inhibit the progression of prostate 51,52 , breast 49,50,103 , ovarian 35 , lung 108,109 , pancreatic 24,57 , and colon cancer 110 , neuroblastomas 53,54 , and leukaemia 58,59 . β-blockade can also inhibit systemic SNS influences on cancer progression such as haematopoietic production of pro-metastatic monocytes 7,27,49 and bone marrow receptivity to metastatic colonization 11,103 .…”

Repurposing Drugs in Oncology (ReDO)—Propranolol as an anti-cancer agent

“…Lin et al showed that chronic restraint stress promoted tumour growth in xenograft models of colorectal cancer, and that this effect could be blocked, in vivo, using PRO at a dose of 2 mg/kg [58]. …”