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

TitleChronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma.
Publication TypeJournal Article
Year of Publication2006
AuthorsThaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R, Lu C, Jennings NB, Armaiz-Pena G, Bankson JA, Ravoori M, Merritt WM, Lin YG, Mangala LS, Kim TJin, Coleman RL, Landen CN, Li Y, Felix E, Sanguino AM, Newman RA, Lloyd M, Gershenson DM, Kundra V, Lopez-Berestein G, Lutgendorf SK, Cole SW, Sood AK
JournalNat Med
Date Published2006 Aug
KeywordsAnimals, Carcinoma, Cell Line, Tumor, Disease Models, Animal, Drug Combinations, Enzyme Inhibitors, Female, Humans, Isoproterenol, Mice, Mice, Nude, Neoplasm Transplantation, Neovascularization, Pathologic, Organ Size, Ovarian Neoplasms, Phthalazines, Pyridines, Random Allocation, Stress, Psychological, Terbutaline, Transplantation, Heterologous, Tumor Burden, Vascular Endothelial Growth Factor A

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 beta(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 beta-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.

Alternate JournalNat. Med.
PubMed ID16862152
Grant List2P50 CA083639-06A1 / CA / NCI NIH HHS / United States
AI52737 / AI / NIAID NIH HHS / United States
CA-104825 / CA / NCI NIH HHS / United States
CA-10929801 / CA / NCI NIH HHS / United States
CA-11079301 / CA / NCI NIH HHS / United States