Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma

Premal H. Thaker, Liz Y. Han, Aparna A. Kamat, Jesusa M. Arevalo, Rie Takahashi, Chunhua Lu, Nicholas B. Jennings, Guillermo Armaiz-Pena, James A. Bankson, Murali Ravoori, William M. Merritt, Yvonne G. Lin, Lingegowda S. Mangala, Tae Jin Kim, Robert L. Coleman, Charles N. Landen, Yang Li, Edward Felix, Angela M. Sanguino, Robert A. NewmanMary Lloyd, David M. Gershenson, Vikas Kundra, Gabriel Lopez-Berestein, Susan K. Lutgendorf, Steven W. Cole, Anil K. Sood

Research output: Contribution to journalArticle

735 Scopus citations

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 β2 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 β-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.

Original languageEnglish
Pages (from-to)939-944
Number of pages6
JournalNature medicine
Volume12
Issue number8
DOIs
StatePublished - Aug 1 2006
Externally publishedYes

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    Thaker, P. H., Han, L. Y., Kamat, A. A., Arevalo, J. M., Takahashi, R., Lu, C., Jennings, N. B., Armaiz-Pena, G., Bankson, J. A., Ravoori, M., Merritt, W. M., Lin, Y. G., Mangala, L. S., Kim, T. J., Coleman, R. L., Landen, C. N., Li, Y., Felix, E., Sanguino, A. M., ... Sood, A. K. (2006). Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nature medicine, 12(8), 939-944. https://doi.org/10.1038/nm1447