Role of transforming growth factor-β1 pathway in angiogenesis induced by chronic stress in colorectal cancer

作者全名：Zhang, Jie; Deng, Yao-Tiao; Liu, Jie; Gan, Lu; Jiang, Yu

作者地址：[Zhang, Jie; Gan, Lu] Chongqing Med Univ, Affiliated Hosp 1, Dept Oncol, Chongqing, Peoples R China; [Deng, Yao-Tiao; Liu, Jie; Jiang, Yu] Sichuan Univ, West China Hosp, Canc Ctr, Dept Med Oncol, Chengdu, Peoples R China; [Gan, Lu] 1 Youyi Rd, Chongqing 400016, Peoples R China; [Jiang, Yu] 37 Guo Xue Xiang, Chengdu 610041, Sichuan, Peoples R China

通信作者：Gan, L (通讯作者)，1 Youyi Rd, Chongqing 400016, Peoples R China.; Jiang, Y (通讯作者)，37 Guo Xue Xiang, Chengdu 610041, Sichuan, Peoples R China.

来源：CANCER BIOLOGY & THERAPY

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001243133400001

JCR分区：Q2

影响因子：4.4

年份：2024

卷号：25

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Chronic stress; norepinephrine; transforming growth factor-beta 1; hypoxia inducible factor-1 alpha; angiogenesis

摘要：BackgroundChronic stress can induce stress-related hormones; norepinephrine (NE) is considered to have the highest potential in cancer. NE can stimulate the expression of hypoxia-inducible factor-1 alpha (HIF-1 alpha), which is associated with vascular endothelial growth factor (VEGF) secretion and tumor angiogenesis. However, the underlying mechanisms are poorly understood.MethodsTumor-bearing mice were subjected to chronic restraint stress and treated with normal saline, human monoclonal VEGF-A neutralizing antibody bevacizumab, or beta-adrenergic receptor (beta-AR) antagonist (propranolol). Tumor growth and vessel density were also evaluated. Human colorectal adenocarcinoma cells were treated with NE, propranolol, or the inhibitor of transforming growth factor-beta (TGF-beta) receptor Type I kinase (Ly2157299) in vitro. TGF-beta 1 in mouse serum and cell culture supernatants was quantified using ELISA. The expression of HIF-1 alpha was measured using Real time-PCR and western blotting. Cell migration and invasion were tested.ResultsChronic restraint stress attenuated the efficacy of bevacizumab and promoted tumor growth and angiogenesis in a colorectal tumor model. Propranolol blocked this effect and inhibited TGF-beta 1 elevation caused by chronic restraint stress or NE. NE upregulated HIF-1 alpha expression, which was reversed by propranolol or Ly2157299. Propranolol and Ly2157199 blocked NE-stimulated cancer cell migration and invasion.ConclusionsOur results demonstrate the effect of NE on tumor angiogenesis and the critical role of TGF-beta 1 signaling during this process. In addition, beta-AR/TGF-beta 1 signaling/HIF-1 alpha/VEGF is a potential signaling pathway. This study also indicates that psychosocial stress might be a risk factor which weakens the efficacy of anti-angiogenic therapy.

基金机构：National Natural Science Foundation of China [81572853, 81703083]

基金资助正文：This study was supported by the National Natural Science Foundation of China [grant numbers: 81572853 and 81703083]