title: Biobehavioral influences on matrix metalloproteinase expression in ovarian carcinoma.
abstract: OBJECTIVE
  Stromal cells in the tumor microenvironment, such as macrophages, play an active role in tumor growth and angiogenesis. However, little is known about relationships of biobehavioral factors with angiogenic cytokines and matrix metalloproteinases (MMP) produced by stromal cells. This study examined distress, MMPs, and angiogenic cytokines in ovarian cancer patients and in vitro.
  
  
  METHODS
  Patients suspected of ovarian cancer completed preoperative questionnaires. At surgery, 56 were confirmed to have epithelial ovarian cancer. Tumor samples were analyzed for macrophage (CD68(+)) and tumor cell levels of MMP-2, MMP-9, and vascular endothelial growth factor. In vitro stimulation of isolated macrophage cells by the stress hormones norepinephrine and cortisol was done to assess effects on MMP-9.
  
  
  RESULTS
  Depressed patients showed significant elevations of MMP-9 in CD68(+) cells, adjusting for stage (P<0.0001). Patients with higher levels of current stress (P=0.01), life stress over the last 6 months (P=0.004), and general negative affect (P=0.007) also showed significantly greater MMP-9 in CD68(+) cells. In contrast, higher social support was associated with lower levels of MMP-9 (P=0.023) and vascular endothelial growth factor (P=0.036) in tumor cells. In vitro analyses showed that macrophage MMP-9 production could be directly enhanced (up to a 2-fold increase) by the stress hormones norepinephrine and cortisol.
  
  
  CONCLUSIONS
  Ovarian cancer patients with elevated depressive symptoms, chronic stress, and low social support showed elevations in MMP-9 in tumor-associated macrophages. Direct in vitro enhancement of stromal MMP-9 production by stress hormones was also shown. These findings may have implications for patient outcomes in ovarian cancer.
authors.affiliation: Department of Psychology, University of Iowa, Iowa City, Iowa 52242, USA. susan-lutgendorf@uiowa.edu
authors.forename: Susan K
authors.initials: SK
authors.lastname: Lutgendorf
authors.forename: Donald M
authors.initials: DM
authors.lastname: Lamkin
authors.forename: Nicholas B
authors.initials: NB
authors.lastname: Jennings
authors.forename: Jesusa M G
authors.initials: JM
authors.lastname: Arevalo
authors.forename: Frank
authors.initials: F
authors.lastname: Penedo
authors.forename: Koen
authors.initials: K
authors.lastname: DeGeest
authors.forename: Robert R
authors.initials: RR
authors.lastname: Langley
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Lucci
authors.forename: Steve W
authors.initials: SW
authors.lastname: Cole
authors.forename: David M
authors.initials: DM
authors.lastname: Lubaroff
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001519:Behavior; D003863:Depression / Q000150:complications / Q000201:enzymology; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008875:Middle Aged; D019964:Mood Disorders / Q000150:complications / Q000201:enzymology; D009638:Norepinephrine / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000150:complications / Q000201:enzymology*; D012944:Social Support; D013315:Stress, Psychological / Q000150:complications / Q000201:enzymology*
chemical_list: D020782:Matrix Metalloproteinases; D006854:Hydrocortisone; D009638:Norepinephrine