title: The effect of chronic stress on anti-angiogenesis of sunitinib in colorectal cancer models.
abstract: Epidemiological and experimental evidence has shown that psychological stress can propel cancer progression. However, its role in anti-angiogenic therapy is not well understood. We previously found that exogenous norepinephrine attenuated the effect of sunitinib, a multi-targeted anti-angiogenic agent, in a mouse melanoma model. Here, we further evaluated the effects of chronic stress on sunitinib therapy in colorectal cancer models. We found that chronic restraint stress markedly weakened the efficacy of sunitinib, primarily through promoting the expression of vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8) to stimulate tumor angiogenesis in vivo. This effect could be sufficiently mimicked by exogenous norepinephrine and blocked by the β-antagonist propranolol. In vitro, norepinephrine up-regulated expression of VEGF and IL-8 in sunitinib-treated cancer cells mainly through the β-adrenoceptor-cAMP-PKA signaling pathway. Norepinephrine also abrogated sunitinib-induced inhibition of cancer cell migration, but had no effect on direct anti-proliferative activity of sunitinib on cancer cells. These findings suggest that psychological stress might attenuate anti-angiogenic therapy primarily through activating beta-adrenergic signaling to promote tumor angiogenesis. It is also suggested that β-blockers might improve anti-angiogenic outcome under psychological stress.
authors.affiliation: Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Guo-Hua
authors.initials: GH
authors.lastname: Deng
authors.affiliation: Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Xiang-Yu
authors.initials: XY
authors.lastname: Xia
authors.affiliation: Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Xin-Mei
authors.initials: XM
authors.lastname: Luo
authors.affiliation: Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Yao-Tiao
authors.initials: YT
authors.lastname: Deng
authors.affiliation: Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Sha-Sha
authors.initials: SS
authors.lastname: He
authors.affiliation: Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Yin-Yan
authors.initials: YY
authors.lastname: Mao
authors.affiliation: Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Xing-Chen
authors.initials: XC
authors.lastname: Peng
authors.affiliation: Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.
authors.forename: Yu-Quan
authors.initials: YQ
authors.lastname: Wei
authors.affiliation: Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China. Electronic address: jiangyu1973@hotmail.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000378:metabolism*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D002908:Chronic Disease; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D016209:Interleukin-8 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009638:Norepinephrine / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015398:Signal Transduction; D013315:Stress, Psychological; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000316:Adrenergic alpha-Agonists; D020533:Angiogenesis Inhibitors; C508606:CXCL8 protein, human; D007211:Indoles; D016209:Interleukin-8; D011758:Pyrroles; D011943:Receptors, Adrenergic, beta; D042461:Vascular Endothelial Growth Factor A; D000077210:Sunitinib; D009638:Norepinephrine
keywords: Adrenoceptor; Anti-angiogenic therapy; Chronic stress; Norepinephrine; Sunitinib