title: Stress hormone-mediated invasion of ovarian cancer cells.
abstract: OBJECTIVE
  There is growing evidence that stress and other behavioral factors may affect cancer progression and patient survival. The underlying mechanisms for this association are poorly understood. The purpose of this study is to determine the effects of stress-associated hormones norepinephrine, epinephrine, and cortisol on the invasive potential of ovarian cancer cells.
  
  
  METHODS
  The ovarian cancer cells EG, SKOV3, and 222 were exposed to increasing levels of either norepinephrine, epinephrine, or cortisol, and the in vitro invasive potential was determined using the membrane invasion culture system. Additionally, the effects of these stress hormones on matrix metalloproteinase-2 (MMP-2) and MMP-9 were determined by ELISA. The effects of the beta-adrenergic agonist isoproterenol on in vivo tumor growth were determined using nude mice.
  
  
  RESULTS
  Stress levels of norepinephrine increased the in vitro invasiveness of ovarian cancer cells by 89% to 198%. Epinephrine also induced significant increases in invasion in all three cell lines ranging from 64% to 76%. Cortisol did not significantly affect invasiveness of the EG and 222 cell lines but increased invasion in the SKOV3 cell line (P = 0.01). We have previously shown that ovarian cancer cells express beta-adrenergic receptors. The beta-adrenergic antagonist propanolol (1 mumol/L) completely blocked the norepinephrine-induced increase in invasiveness. Norepinephrine also increased tumor cell expression of MMP-2 (P = 0.02 for both SKOV3 and EG cells) and MMP-9 (P = 0.01 and 0.04, respectively), and pharmacologic blockade of MMPs abrogated the effects of norepinephrine on tumor cell invasive potential. Isoproterenol treatment resulted in a significant increase in tumor volume and infiltration in the SKOV3ip1 in vivo model, which was blocked by propranolol.
  
  
  CONCLUSIONS
  These findings provide direct experimental evidence that stress hormones can enhance the invasive potential of ovarian cancer cells. These effects are most likely mediated by stimulation of MMPs.
authors.affiliation: Department of Gynecologic Oncology, The University of Texas M.D. Anderson Cancer Center, PO Box 301439, Houston, TX 77230, USA. asood@mdanderson.org
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.forename: Robert
authors.initials: R
authors.lastname: Bhatty
authors.forename: Aparna A
authors.initials: AA
authors.lastname: Kamat
authors.forename: Charles N
authors.initials: CN
authors.lastname: Landen
authors.forename: Liz
authors.initials: L
authors.lastname: Han
authors.forename: Premal H
authors.initials: PH
authors.lastname: Thaker
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: David M
authors.initials: DM
authors.lastname: Gershenson
authors.forename: Susan
authors.initials: S
authors.lastname: Lutgendorf
authors.forename: Steven W
authors.initials: SW
authors.lastname: Cole
mesh_terms: D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D004837:Epinephrine / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009638:Norepinephrine / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000473:pathology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology
chemical_list: D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D007545:Isoproterenol; D006854:Hydrocortisone; D009638:Norepinephrine; D004837:Epinephrine