Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2020

01-12-2020 | Hepatocellular Carcinoma | Research

Norepinephrine-stimulated HSCs secrete sFRP1 to promote HCC progression following chronic stress via augmentation of a Wnt16B/β-catenin positive feedback loop

Authors: Xia-Hui Lin, Hua-Hua Liu, Shu-Jung Hsu, Rui Zhang, Jie Chen, Jun Chen, Dong-Mei Gao, Jie-Feng Cui, Zheng-Gang Ren, Rong-Xin Chen

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2020

Login to get access

Abstract

Background

Sustained adrenergic signaling secondary to chronic stress promotes cancer progression; however, the underlying mechanisms for this phenomenon remain unclear. Hepatocellular carcinoma (HCC) frequently develops within fibrotic livers rich in activated hepatic stellate cells (HSCs). Here, we examined whether the stress hormone norepinephrine (NE) could accelerate HCC progression by modulating HSCs activities.

Methods

HCC cells were exposed to conditioned medium (CM) from NE-stimulated HSCs. The changes in cell migration and invasion, epithelial-mesenchymal transition, parameters of cell proliferation, and levels of cancer stem cell markers were analyzed. Moreover, the in vivo tumor progression of HCC cells inoculated with HSCs was studied in nude mice subjected to chronic restraint stress.

Results

CM from NE-treated HSCs significantly promoted cell migration and invasion, epithelial-mesenchymal transition (EMT), and expression of cell proliferation-related genes and cancer stem cell markers in HCC cells. These pro-tumoral effects were markedly reduced by depleting secreted frizzled related protein 1 (sFRP1) in CM. The pro-tumoral functions of sFRP1 were dependent on β-catenin activation, and sFRP1 augmented the binding of Wnt16B to its receptor FZD7, resulting in enhanced β-catenin activity. Additionally, sFRP1 enhanced Wnt16B expression, reinforcing an autocrine feedback loop of Wnt16B/β-catenin signaling. The expression of sFRP1 in HSCs promoted HCC progression in an in vivo model under chronic restraint stress, which was largely attenuated by sFRP1 knockdown.

Conclusions

We identify a new mechanism by which chronic stress promotes HCC progression. In this model, NE activates HSCs to secrete sFRP1, which cooperates with a Wnt16B/β-catenin positive feedback loop. Our findings have therapeutic implications for the treatment of chronic stress-promoted HCC progression.
Appendix
Available only for authorised users
Literature
1.
Le CP, Nowell CJ, Kim-Fuchs C, Botteri E, Hiller JG, Ismail H, et al. Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination. Nat Commun. 2016;7(undefined):10634.PubMedPubMedCentralCrossRef
2.
Powell ND, Tarr AJ, Sheridan JF. Psychosocial stress and inflammation in cancer. Brain Behav Immun. 2013;null(undefined):S41–7.CrossRef
3.
Gjyshi A, Dash S, Cen L, Cheng CH, Zhang C, Yoder SJ, et al. Early transcriptional response of human ovarian and fallopian tube surface epithelial cells to norepinephrine. Sci Rep. 2018;8(1):8291.PubMedPubMedCentralCrossRef
4.
Cui B, Luo Y, Tian P, Peng F, Lu J, Yang Y, et al. Stress-induced epinephrine enhances lactate dehydrogenase a and promotes breast cancer stem-like cells. J Clin Invest. 2019;129(3):1030–46.PubMedPubMedCentralCrossRef
5.
Nilsson MB, Sun H, Diao L, Tong P, Liu D, Li L, et al. Stress hormones promote EGFR inhibitor resistance in NSCLC: Implications for combinations with β-blockers. Sci Transl Med. 2017;9(415):undefined.CrossRef
6.
Wurtman RJ. Stress and the adrenocortical control of epinephrine synthesis. Metabolism. 2002;51(null):11–4.PubMedCrossRef
7.
Thaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R, Lu C, et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med. 2006;12(8):939–44.PubMedCrossRef
8.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.PubMedCrossRef
9.
Krizhanovsky V, Yon M, Dickins RA, Hearn S, Simon J, Miething C, et al. Senescence of activated stellate cells limits liver fibrosis. Cell. 2008;134(4):657–67.PubMedPubMedCentralCrossRef
10.
Zhang DY, Friedman SL. Fibrosis-dependent mechanisms of hepatocarcinogenesis. Hepatology (Baltimore, Md). 2012;56(2):769–75.CrossRef
11.
Hernandez-Gea V, Friedman SL. Pathogenesis of liver fibrosis. Annu Rev Pathol. 2011;6(undefined):425–56.PubMedCrossRef
12.
Kang N, Gores GJ, Shah VH. Hepatic stellate cells: partners in crime for liver metastases? Hepatology (Baltimore, Md). 2011;54(2):707–13.CrossRef
13.
Loréal O, Levavasseur F, Fromaget C, Gros D, Guillouzo A, Clément B. Cooperation of Ito cells and hepatocytes in the deposition of an extracellular matrix in vitro. Am J Pathol. 1993;143(2):538–44.PubMedPubMedCentral
14.
Coulouarn C, Corlu A, Glaise D, Guenon I, Thorgeirsson SS, Clement B. Hepatocyte-stellate cell cross-talk in the liver engenders a permissive inflammatory microenvironment that drives progression in hepatocellular carcinoma. Cancer Res. 2012;72(10):2533–42.PubMedPubMedCentralCrossRef
15.
Wright JH, Johnson MM, Shimizu-Albergine M, Bauer RL, Hayes BJ, Surapisitchat J, et al. Paracrine activation of hepatic stellate cells in platelet-derived growth factor C transgenic mice: evidence for stromal induction of hepatocellular carcinoma. Int J Cancer. 2014;134(4):778–88.PubMedCrossRef
16.
Yang JD, Nakamura I, Roberts LR. The tumor microenvironment in hepatocellular carcinoma: current status and therapeutic targets. Semin Cancer Biol. 2011;21(1):35–43.PubMedCrossRef
17.
Makino Y, Hikita H, Kodama T, Shigekawa M, Yamada R, Sakamori R, et al. CTGF mediates tumor-Stroma interactions between Hepatoma cells and hepatic stellate cells to accelerate HCC progression. Cancer Res. 2018;78(17):4902–14.PubMedCrossRef
18.
Ondicova K, Mravec B. Role of nervous system in cancer aetiopathogenesis. Lancet Oncol. 2010;11(6):596–601.PubMedCrossRef
19.
Jobling P, Pundavela J, Oliveira SM, Roselli S, Walker MM, Hondermarck H. Nerve-Cancer cell cross-talk: a novel promoter of tumor progression. Cancer Res. 2015;75(9):1777–81.PubMedCrossRef
20.
Oben JA, Roskams T, Yang S, Lin H, Sinelli N, Torbenson M, et al. Hepatic fibrogenesis requires sympathetic neurotransmitters. Gut. 2004;53(3):438–45.PubMedPubMedCentralCrossRef
21.
Sancho-Bru P, Bataller R, Colmenero J, Gasull X, Moreno M, Arroyo V, et al. Norepinephrine induces calcium spikes and proinflammatory actions in human hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2006;291(5):G877–84.PubMedCrossRef
22.
Bioulac-Sage P, Lafon ME, Saric J, Balabaud C. Nerves and perisinusoidal cells in human liver. J Hepatol. 1990;10(1):105–12.PubMedCrossRef
23.
vom Dahl S, Bode JG, Reinehr RM, Mönnighoff I, Kubitz R, Häussinger D. Release of osmolytes from perfused rat liver on perivascular nerve stimulation: alpha-adrenergic control of osmolyte efflux from parenchymal and nonparenchymal liver cells. Hepatology (Baltimore, Md). 1999;29(1):195–204.CrossRef
24.
Athari A, Hänecke K, Jungermann K. Prostaglandin F2 alpha and D2 release from primary Ito cell cultures after stimulation with noradrenaline and ATP but not adenosine. Hepatology (Baltimore, Md). 1994;20(null):142–8.
25.
Liu N, Zhang XL, Liang CD, Yao DM, Liu L, Zhao DQ, et al. Dynamic changes of alpha-AR, beta1-AR and beta2-AR expression during hepatic fibrogenesis. Zhonghua Gan Zang Bing Za Zhi = Chin J Hepatol. 2009;17(9):653–6.
26.
Kawai Y, Powell A, Arinze IJ. Adrenergic receptors in human liver plasma membranes: predominance of beta 2- and alpha 1-receptor subtypes. J Clin Endocrinol Metab. 1986;62(5):827–32.PubMedCrossRef
27.
Zhang R, Lin XH, Ma M, Chen J, Chen J, Gao DM, et al. Periostin involved in the activated hepatic stellate cells-induced progression of residual hepatocellular carcinoma after sublethal heat treatment: its role and potential for therapeutic inhibition. J Transl Med. 2018;16(1):302.PubMedPubMedCentralCrossRef
28.
Szpunar MJ, Burke KA, Dawes RP, Brown EB, Madden KS. The antidepressant desipramine and α2-adrenergic receptor activation promote breast tumor progression in association with altered collagen structure. Cancer Prev Res (Philadelphia, Pa). 2013;6(12):1262–72.CrossRef
29.
Pez F, Lopez A, Kim M, Wands JR, Caron de Fromentel C, Merle P. Wnt signaling and hepatocarcinogenesis: molecular targets for the development of innovative anticancer drugs. J Hepatol. 2013;59(5):1107–17.PubMedCrossRef
30.
31.
Uren A, Reichsman F, Anest V, Taylor WG, Muraiso K, Bottaro DP, et al. Secreted frizzled-related protein-1 binds directly to wingless and is a biphasic modulator of Wnt signaling. J Biol Chem. 2000;275(6):4374–82.PubMedCrossRef
32.
Stojkov NJ, Baburski AZ, Bjelic MM, Sokanovic SJ, Mihajlovic AI, Drljaca DM, et al. In vivo blockade of α1-adrenergic receptors mitigates stress-disturbed cAMP and cGMP signaling in Leydig cells. Mol Hum Reprod. 2014;20(1):77–88.PubMedCrossRef
33.
Bovolenta P, Esteve P, Ruiz JM, Cisneros E, Lopez-Rios J. Beyond Wnt inhibition: new functions of secreted frizzled-related proteins in development and disease. J Cell Sci. 2008;121:737–46.PubMedCrossRef
34.
Perugorria MJ, Olaizola P, Labiano I, Esparza-Baquer A, Marzioni M, Marin JJG, et al. Wnt-β-catenin signalling in liver development, health and disease. Nat Rev Gastroenterol Hepatol. 2019;16(2):121–36.PubMedCrossRef
35.
Nusse R, Clevers H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell. 2017;169(6):985–99.PubMedCrossRef
36.
37.
Andersen BL, Farrar WB, Golden-Kreutz D, Kutz LA, MacCallum R, Courtney ME, et al. Stress and immune responses after surgical treatment for regional breast cancer. J Natl Cancer Inst. 1998;90(1):30–6.PubMedCrossRef
38.
Reiche EM, Nunes SO, Morimoto HK. Stress, depression, the immune system, and cancer. Lancet Oncol. 2004;5(10):617–25.PubMedCrossRef
39.
Jansen AS, Nguyen XV, Karpitskiy V, Mettenleiter TC, Loewy AD. Central command neurons of the sympathetic nervous system: basis of the fight-or-flight response. Science (New York, NY). 1995;270(5236):644–6.CrossRef
40.
Reves JG, Karp RB, Buttner EE, Tosone S, Smith LR, Samuelson PN, et al. Neuronal and adrenomedullary catecholamine release in response to cardiopulmonary bypass in man. Circulation. 1982;66(1):49–55.PubMedCrossRef
41.
Snider SR, Kuchel O. Dopamine: an important neurohormone of the sympathoadrenal system. Significance of increased peripheral dopamine release for the human stress response and hypertension. Endocr Rev. 1983;4(3):291–309.PubMedCrossRef
42.
Carbone E, Borges R, Eiden LE, García AG, Hernández-Cruz A. Chromaffin cells of the adrenal medulla: physiology, pharmacology, and disease. Comprehensive Physiology. 2019;9(4):1443–502.PubMedCrossRef
43.
Wu FQ, Fang T, Yu LX, Lv GS, Lv HW, Liang D, et al. ADRB2 signaling promotes HCC progression and sorafenib resistance by inhibiting autophagic degradation of HIF1α. J Hepatol. 2016;65(2):314–24.PubMedCrossRef
44.
Han C, Bowen WC, Michalopoulos GK, Wu T. Alpha-1 adrenergic receptor transactivates signal transducer and activator of transcription-3 (Stat3) through activation of Src and epidermal growth factor receptor (EGFR) in hepatocytes. J Cell Physiol. 2008;216(2):486–97.PubMedPubMedCentralCrossRef
45.
Yang EV, Kim SJ, Donovan EL, Chen M, Gross AC, Webster Marketon JI, et al. Norepinephrine upregulates VEGF, IL-8, and IL-6 expression in human melanoma tumor cell lines: implications for stress-related enhancement of tumor progression. Brain Behav Immun. 2009;23(2):267–75.PubMedCrossRef
46.
Huan HB, Wen XD, Chen XJ, Wu L, Wu LL, Zhang L, et al. Sympathetic nervous system promotes hepatocarcinogenesis by modulating inflammation through activation of alpha1-adrenergic receptors of Kupffer cells. Brain Behav Immun. 2017;59(undefined):118–34.PubMedCrossRef
47.
Eng JW, Kokolus KM, Reed CB, Hylander BL, Ma WW, Repasky EA. A nervous tumor microenvironment: the impact of adrenergic stress on cancer cells, immunosuppression, and immunotherapeutic response. Cancer Immunol Immunother. 2014;63(11):1115–28.PubMedPubMedCentralCrossRef
48.
Liu TT, Ding TL, Ma Y, Wei W. Selective α1B- and α1D-adrenoceptor antagonists suppress noradrenaline-induced activation, proliferation and ECM secretion of rat hepatic stellate cells in vitro. Acta Pharmacol Sin. 2014;35(11):1385–92.PubMedPubMedCentralCrossRef
49.
Chida Y, Sudo N, Kubo C. Does stress exacerbate liver diseases? J Gastroenterol Hepatol. 2006;21(null):202–8.PubMedCrossRef
50.
Caldwell GM, Jones C, Gensberg K, Jan S, Hardy RG, Byrd P, et al. The Wnt antagonist sFRP1 in colorectal tumorigenesis. Cancer Res. 2004;64(3):883–8.PubMedCrossRef
51.
Fukui T, Kondo M, Ito G, Maeda O, Sato N, Yoshioka H, et al. Transcriptional silencing of secreted frizzled related protein 1 (SFRP 1) by promoter hypermethylation in non-small-cell lung cancer. Oncogene. 2005;24(41):6323–7.PubMedCrossRef
52.
Quan H, Zhou F, Nie D, Chen Q, Cai X, Shan X, et al. Hepatitis C virus core protein epigenetically silences SFRP1 and enhances HCC aggressiveness by inducing epithelial-mesenchymal transition. Oncogene. 2014;33(22):2826–35.PubMedCrossRef
53.
Davaadorj M, Imura S, Saito YU, Morine Y, Ikemoto T, Yamada S, et al. Loss of SFRP1 expression is associated with poor prognosis in hepatocellular carcinoma. Anticancer Res. 2016;36(2):659–64.PubMed
54.
Liang CJ, Wang ZW, Chang YW, Lee KC, Lin WH, Lee JL. SFRPs Are Biphasic Modulators of Wnt-Signaling-Elicited Cancer Stem Cell Properties beyond Extracellular Control. Cell Rep. 2019;28(6):1511–25.e5.PubMedCrossRef
55.
Joesting MS, Perrin S, Elenbaas B, Fawell SE, Rubin JS, Franco OE, et al. Identification of SFRP1 as a candidate mediator of stromal-to-epithelial signaling in prostate cancer. Cancer Res. 2005;65(22):10423–30.PubMedCrossRef
56.
Qu Y, Ray PS, Li J, Cai Q, Bagaria SP, Moran C, et al. High levels of secreted frizzled-related protein 1 correlate with poor prognosis and promote tumourigenesis in gastric cancer. Eur J Cancer (Oxford, England: 1990). 2013;49(17):3718–28.CrossRef
57.
Bevilacqua M, Norbiato G, Chebat E, Baldi G, Bertora P, Regalia E, et al. Changes in alpha-1 and beta-2 adrenoceptor density in human hepatocellular carcinoma. Cancer. 1991;67(10):2543–51.PubMedCrossRef
Metadata
Title
Norepinephrine-stimulated HSCs secrete sFRP1 to promote HCC progression following chronic stress via augmentation of a Wnt16B/β-catenin positive feedback loop
Authors
Xia-Hui Lin
Hua-Hua Liu
Shu-Jung Hsu
Rui Zhang
Jie Chen
Jun Chen
Dong-Mei Gao
Jie-Feng Cui
Zheng-Gang Ren
Rong-Xin Chen
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2020
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-020-01568-0

Other articles of this Issue 1/2020

Journal of Experimental & Clinical Cancer Research 1/2020 Go to the issue

Research

miR-615-3p promotes the epithelial-mesenchymal transition and metastasis of breast cancer by targeting PICK1/TGFBRI axis

Correction

Correction to: LncRNA MYLK-AS1 facilitates tumor progression and angiogenesis by targeting miR-424-5p/E2F7 axis and activating VEGFR-2 signaling pathway in hepatocellular carcinoma

Review

Dexosomes as a cell-free vaccine for cancer immunotherapy

Retraction Note

Retraction Note: Long noncoding RNA MLK7-AS1 promotes ovarian cancer cells progression by modulating miR-375/YAP1 axis

Review

The biomarkers related to immune related adverse events caused by immune checkpoint inhibitors

Review

The role of microenvironment in tumor angiogenesis
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits