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Biobehavioral Influences on Matrix Metalloproteinase Expression in Ovarian Carcinoma

Authors' Affiliations: Departments of ¹ Psychology, ² Obstetrics and Gynecology, and ³ Urology and ⁴ Holden Comprehensive Cancer Center, University of Iowa; ⁵ Department of Microbiology, University of Iowa, and Department of Veterans Affairs Medical Center, Iowa City, Iowa; Departments of ⁶ Gynecologic Oncology and ⁷ Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; ⁸ Division of Hematology-Oncology, David Geffen School of Medicine, University of California at Los Angeles School of Medicine; ⁹ The Norman Cousins Center, Jonsson Comprehensive Cancer Center, University of California at Los Angeles AIDS Institute, and University of California at Los Angeles Molecular Biology Institute, Los Angeles, California; and ¹⁰ Department of Psychology and ¹¹ Division of Gynecologic Oncology and ¹² Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida

Requests for reprints: Susan K. Lutgendorf, Department of Psychology, University of Iowa, E11 Seashore Hall, Iowa City, IA 52242. Phone: 319-335-2432; Fax: 319-335-0191; E-mail: susan-lutgendorf{at}uiowa.edu.

Purpose: 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.

Experimental Design: 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.

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