Nature Medicine
- 12, 939 - 944 (2006)
Published online: 23 July 2006; | doi:10.1038/nm1447
Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinomaPremal H Thaker1, 10, Liz Y Han1, 10, Aparna A Kamat1, 10, Jesusa M Arevalo2, Rie Takahashi2, Chunhua Lu1, Nicholas B Jennings1, Guillermo Armaiz-Pena1, James A Bankson3, Murali Ravoori4, William M Merritt1, Yvonne G Lin1, Lingegowda S Mangala1, Tae Jin Kim1, Robert L Coleman1, Charles N Landen1, Yang Li1, Edward Felix5, Angela M Sanguino6, Robert A Newman5, Mary Lloyd7, David M Gershenson1, Vikas Kundra4, 8, Gabriel Lopez-Berestein6, Susan K Lutgendorf9, Steven W Cole2 & Anil K Sood1, 71
Department of Gynecologic Oncology, University of Texas (U.T.) M.D. Anderson Cancer Center, 1155 Herman Pressler, Unit 1362, Houston, Texas 77030, USA. 2
Division of Hematology-Oncology, Department of Medicine, 11-934 Factor Building, University of California Los Angeles (UCLA) School of Medicine, Los Angeles, California 90095, USA. 3
Department of Imaging Physics, U.T. M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. 4
Department of Experimental Diagnostic Imaging, U.T. M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. 5
Department of Experimental Therapeutics, U.T. M.D. Anderson Cancer Center, 8000 El Rio Street, Houston, Texas 77054, USA. 6
Department of Experimental Therapeutics, U.T. M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. 7
Department of Cancer Biology, U.T. M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. 8
Department of Diagnostic Radiology, U.T. M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. 9
Department of Psychology, University of Iowa, E228 Seashore Hall, Iowa City, Iowa 52241, USA. 10
These authors contributed equally to this work.
Correspondence should be addressed to Anil K Sood asood@mdanderson.org 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  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 -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.
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