Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma

Nat Med. 2006 Aug;12(8):939-44. doi: 10.1038/nm1447. Epub 2006 Jul 23.


Stress can alter immunological, neurochemical and endocrinological functions, but its role in cancer progression is not well understood. Here, we show that chronic behavioral stress results in higher levels of tissue catecholamines, greater tumor burden and more invasive growth of ovarian carcinoma cells in an orthotopic mouse model. These effects are mediated primarily through activation of the tumor cell cyclic AMP (cAMP)-protein kinase A (PKA) signaling pathway by the beta(2) adrenergic receptor (encoded by ADRB2). Tumors in stressed animals showed markedly increased vascularization and enhanced expression of VEGF, MMP2 and MMP9, and we found that angiogenic processes mediated the effects of stress on tumor growth in vivo. These data identify beta-adrenergic activation of the cAMP-PKA signaling pathway as a major mechanism by which behavioral stress can enhance tumor angiogenesis in vivo and thereby promote malignant cell growth. These data also suggest that blocking ADRB-mediated angiogenesis could have therapeutic implications for the management of ovarian cancer.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma / blood supply*
  • Carcinoma / diagnostic imaging
  • Carcinoma / pathology
  • Carcinoma / physiopathology*
  • Cell Line, Tumor
  • Disease Models, Animal
  • Drug Combinations
  • Enzyme Inhibitors / pharmacology
  • Female
  • Humans
  • Isoproterenol / agonists
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Neovascularization, Pathologic / physiopathology*
  • Organ Size
  • Ovarian Neoplasms / blood supply*
  • Ovarian Neoplasms / diagnostic imaging
  • Ovarian Neoplasms / pathology
  • Ovarian Neoplasms / physiopathology*
  • Phthalazines / pharmacology
  • Pyridines / pharmacology
  • Radiography
  • Random Allocation
  • Stress, Psychological*
  • Terbutaline / agonists
  • Transplantation, Heterologous
  • Tumor Burden
  • Vascular Endothelial Growth Factor A / physiology


  • Drug Combinations
  • Enzyme Inhibitors
  • Phthalazines
  • Pyridines
  • Vascular Endothelial Growth Factor A
  • vatalanib
  • Isoproterenol
  • Terbutaline