Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2015 Oct 7;10(10):e0139978.
doi: 10.1371/journal.pone.0139978. eCollection 2015.

Effect of Chronic Psychological Stress on Liver Metastasis of Colon Cancer in Mice

Lu Zhao  1 , Jianhua Xu  2 , Fang Liang  1 , Ao Li  1 , Yong Zhang  1 , Jue Sun  1
Affiliations

Effect of Chronic Psychological Stress on Liver Metastasis of Colon Cancer in Mice

Lu Zhao et al. PLoS One. .

Abstract

Metastasis to the liver is a main factor in colorectal cancer mortality. Previous studies suggest that chronic psychological stress is important in cancer progression, but its effect on liver metastasis has not been investigated. To address this, we established a liver metastasis model in BALB/c nude mice to investigate the role of chronic stress in liver metastasis. Our data suggest that chronic stress elevates catecholamine levels and promotes liver metastasis. Chronic stress was also associated with increased tumor associated macrophages infiltration into the primary tumor and increased the expression of metastatic genes. Interestingly, β-blocker treatment reversed the effects of chronic stress on liver metastasis. Our results suggest the β-adrenergic signaling pathway is involved in regulating colorectal cancer progression and liver metastasis. Additionally, we submit that adjunctive therapy with a β-blocker may complement existing colorectal cancer therapies.

PubMed Disclaimer

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Chronic restraint stress and drug administration protocol.
(A) Mice in the stress groups were restrained in a special space that prevented them from moving freely. (B) Mice in the stress groups experienced physical restraint for 6 hours per day for 35 days commencing 7 days before tumor cell injection. A β-adrenergic antagonist was given subcutaneously by osmotic minipump. Drug exposure was sustained throughout the experiment. HT–29 cells were injected into the spleen on day 0.
Fig 2
Fig 2. Effect of chronic stress on liver metastasis.
(A) Representative images of spleen taken on day 28 after tumor cell injection. (B) Representative images of metastatic liver taken on day 28 after tumor cell injection. (C) Data represents average spleen weight from the six groups. (D) Data represents average liver weight from the six groups. ** P< 0.01 versus BC group, # P< 0.05 versus BS group.
Fig 3
Fig 3. Effect of chronic stress on catecholamine levels.
(A) Body weights were monitored throughout the experiment. HT–29 cells were injected into the spleen on day 0. (B) Data represent average serum levels of NE and E in BC and BS group, * P< 0.05 versus BC group, ** P< 0.01 versus BC group. (C) Representative images of HPLD-ECD fingerprint of catecholamine levels in spleen tumor tissues in BC and BS group. (D) Data represent average level of NE and E in spleen tumor tissue in BC and BS group, * P< 0.05 versus BC group.
Fig 4
Fig 4. Effect of chronic stress the on the tumor microenvironment.
(A) CD11b+F4/80+ cells were quantified by flow cytometry in HT–29 primary spleen tumors harvested 28 d after injection. (B) Data represents average CD11b+F4/80+ composition in tumors harvested from the spleen. ** P< 0.01 versus BC group, # P < 0.05 versus BS group. (C) MDSCs were quantified by flow cytometry in HT–29 primary spleen tumors harvested 28 d after injection. (D) Data represents average CD11b+GrloLy6Chi composition in tumors harvested from the spleen. *P < 0.05 versus BC group.
Fig 5
Fig 5. Effect of β-adrenergic signaling pathway on metastatic genes.
(A) mRNA expression of TGF-β, IL–6, PTGS2, MMP–9, and VEGF relative to mice in BC group in spleen tumors.** P< 0.01 versus BC group, # P < 0.05 versus BS group, ## P < 0.01 versus BS group. (B) Protein expression of TGF-β, IL–6, PTGS2, MMP–9, and VEGF in spleen tumors. GAPDH was used as a loading control.
Fig 6
Fig 6. Effect of β-adrenergic signaling pathway on tumor vascularization and tissue invasion.
(A)Liver metastatic tumor samples were stained for VEGF by immunohistochemistry. (B) Liver metastatic tumor samples were stained for CD31 by immunohistochemistry. (C) Liver metastatic tumor samples were stained for MMP9 by immunohistochemistry. All photographs were taken at 200×. (D) Mean optical density (OD) of VEGF, CD31, and MMP9 in metastatic liver tumors from mice in the BC, PC, IC, BS, PS, and IS groups. ** P< 0.01 versus BC group, # P < 0.05 versus BS group, ## P < 0.01 versus BS group.
Fig 7
Fig 7. Effect of chronic psychological stress on liver metastasis of colon cancer in mice.
β-adrenergic signaling significantly enhanced tumor cell dissemination to liver, and pharmacologic inhibition of β-adrenergic signaling reduced liver metastasis. Our studies also suggest that propranolol may complement existing therapeutic strategies to slow or prevent liver metastasis from CRC, improving survival of patients who are suffering psychological stress.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015. Jan-Feb;65(1):5–29. 10.3322/caac.21254 - DOI - PubMed
    1. Gallagher DJ, Kemeny N. Metastatic colorectal cancer: from improved survival to potential cure. Oncology. 2010;78(3–4):237–48. 10.1159/000315730 - DOI - PubMed
    1. Kanas GP, Taylor A, Primrose JN, Langeberg WJ, Kelsh MA, Mowat FS, et al. Survival after liver resection in metastatic colorectal cancer: review and meta-analysis of prognostic factors. Clin Epidemiol.2012;4(1):283–301. - PMC - PubMed
    1. Manfredi S, Lepage C, Hatem C, Coatmeur O, Faivre J, Bouvier AM. Epidemiologyand management of liver metastases from colorectal cancer. Ann Surg. 2006. August; 224(2):254–9. - PMC - PubMed
    1. Jansen L, Hoffmeister M, Arndt V, Chang-Claude J, Brenner H. Stage-specific associations between beta blocker use and prognosis after colorectal cancer. Cancer.2014. April;120(8):1178–86. 10.1002/cncr.28546 - DOI - PubMed

Publication types

Substances