title: Social defeat stress promotes tumor growth and angiogenesis by upregulating vascular endothelial growth factor/extracellular signal-regulated kinase/matrix metalloproteinase signaling in a mouse model of lung carcinoma.
abstract: Numerous epidemiological and experimental animal studies have indicated that chronic psychological stress may promote tumor development. However, the underlying molecular mechanisms by which chronic stress promotes tumorigenesis remain to be fully elucidated and animal models have not yet been well established. In the present study, an established mouse model of repeated social defeat stress (RSDS), was generated and used to investigate the effect of stress on tumor growth and metastasis. C57BL/6 mice were exposed to RSDS for 10 days, followed by subcutaneousl inoculation with Lewis lung carcinoma cells for seven days. The tumor weight and volume as well as the number of the lung metastatic nodules were then determined. Vascular endothelial growth factor (VEGF) serum levels were measured using ELISAs. In addition, expression levels of VEGF receptor (VEGFR) and L1 cell adhesion molecule (L1CAM) messenger (m)RNA were confirmed using reverse transcription quantitative polymerase chain reaction. Furthermore, protein expression levels of phosphorlyated extracellular signal-regulated kinase (pERK), matrix metalloproteinase (MMP)-2 and MMP-9 were examined using western blot analysis. The results showed that RSDS significantly increased the weight and the volume of the primary tumor as well as the number of the lung metastatic nodules. Serum VEGF levels were significantly higher in the tumor-stress group compared with those of the unstressed tumor mice. In addition, tumors in stressed animals demonstrated markedly enhanced expression of VEGFR-2 and L1CAM mRNA as well as pERK, MMP-2 and MMP-9 protein expression. In conclusion, these results suggested that RSDS contributed to lung cancer progression, angiogenesis and metastasis, which was partially associated with increased VEGF secretion and therefore the activation of the ERK signaling pathway, resulting in the induction of MMP-2 and MMP-9 protein expression.
authors.affiliation: Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200041, P.R. China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200041, P.R. China.
authors.forename: Bao-Jun
authors.initials: BJ
authors.lastname: Liu
authors.affiliation: Department of Dermatology, Xintai People's Hospital, Xintai, Shandong 271200, P.R. China.
authors.forename: Shumeng
authors.initials: S
authors.lastname: Ji
authors.affiliation: Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200041, P.R. China.
authors.forename: Jing-Feng
authors.initials: JF
authors.lastname: Wu
authors.affiliation: Affiliated Hospital, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310015, P.R. China.
authors.forename: Chang-Qing
authors.initials: CQ
authors.lastname: Xu
authors.affiliation: Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200041, P.R. China.
authors.forename: Yi-Jie
authors.initials: YJ
authors.lastname: Du
authors.affiliation: Department of Childhood and Adolescence, Key Laboratory of Public Health Safety, Ministry of Education, School of Public Health, Fudan University, Shanghai 200032, P.R. China.
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: You
authors.affiliation: Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200041, P.R. China.
authors.forename: Bei
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200041, P.R. China.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Le
authors.affiliation: Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200041, P.R. China.
authors.forename: Hai-Lin
authors.initials: HL
authors.lastname: Xu
authors.affiliation: Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200041, P.R. China.
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Duan
authors.affiliation: Department of Integrative Medicine, Huashan Hospital, Fudan University, Shanghai 200041, P.R. China.
authors.forename: Jing-Cheng
authors.initials: JC
authors.lastname: Dong
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D018827:Carcinoma, Lewis Lung / Q000097:blood / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D020935:MAP Kinase Signaling System / Q000235:genetics; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D051379:Mice; D039842:Neural Cell Adhesion Molecule L1 / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D010766:Phosphorylation; D015398:Signal Transduction; D013315:Stress, Psychological; D015533:Transcriptional Activation; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics
chemical_list: D039842:Neural Cell Adhesion Molecule L1; D040301:Vascular Endothelial Growth Factor Receptor-2; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9