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Letter
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 carcinoma
Premal 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 Sood1,7
Abstract
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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