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

Cancer Biol Ther. 2024 Dec 31;25(1):2366451. doi: 10.1080/15384047.2024.2366451. Epub 2024 Jun 10.

Abstract

Background: Chronic 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-1α (HIF-1α), which is associated with vascular endothelial growth factor (VEGF) secretion and tumor angiogenesis. However, the underlying mechanisms are poorly understood.

Methods: Tumor-bearing mice were subjected to chronic restraint stress and treated with normal saline, human monoclonal VEGF-A neutralizing antibody bevacizumab, or β-adrenergic receptor (β-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-β (TGF-β) receptor Type I kinase (Ly2157299) in vitro. TGF-β1 in mouse serum and cell culture supernatants was quantified using ELISA. The expression of HIF-1α was measured using Real time-PCR and western blotting. Cell migration and invasion were tested.

Results: Chronic 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-β1 elevation caused by chronic restraint stress or NE. NE upregulated HIF-1α expression, which was reversed by propranolol or Ly2157299. Propranolol and Ly2157199 blocked NE-stimulated cancer cell migration and invasion.

Conclusions: Our results demonstrate the effect of NE on tumor angiogenesis and the critical role of TGF-β1 signaling during this process. In addition, β-AR/TGF-β1 signaling/HIF-1α/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.

Keywords: Chronic stress; angiogenesis; hypoxia inducible factor-1α; norepinephrine; transforming growth factor-β1.

MeSH terms

  • Adrenergic beta-Antagonists / pharmacology
  • Adrenergic beta-Antagonists / therapeutic use
  • Angiogenesis
  • Animals
  • Bevacizumab* / pharmacology
  • Bevacizumab* / therapeutic use
  • Cell Line, Tumor
  • Cell Movement
  • Colorectal Neoplasms* / drug therapy
  • Colorectal Neoplasms* / metabolism
  • Colorectal Neoplasms* / pathology
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit* / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit* / metabolism
  • Male
  • Mice
  • Neovascularization, Pathologic* / metabolism
  • Norepinephrine / metabolism
  • Norepinephrine / pharmacology
  • Propranolol / pharmacology
  • Pyrazoles
  • Quinolines
  • Signal Transduction*
  • Stress, Psychological / complications
  • Stress, Psychological / metabolism
  • Transforming Growth Factor beta1* / metabolism
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Transforming Growth Factor beta1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Bevacizumab
  • Propranolol
  • Vascular Endothelial Growth Factor A
  • Norepinephrine
  • LY-2157299
  • Adrenergic beta-Antagonists
  • Pyrazoles
  • Quinolines

Grants and funding

This study was supported by the National Natural Science Foundation of China [grant numbers: 81572853 and 81703083].