Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma.
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.
Thaker
Premal H
PH
Department of Gynecologic Oncology, University of Texas (U.T.) M.D. Anderson Cancer Center, 1155 Herman Pressler, Unit 1362, Houston, Texas 77030, USA.
Han
Liz Y
LY
Kamat
Aparna A
AA
Arevalo
Jesusa M
JM
Takahashi
Rie
R
Lu
Chunhua
C
Jennings
Nicholas B
NB
Armaiz-Pena
Guillermo
G
Bankson
James A
JA
Ravoori
Murali
M
Merritt
William M
WM
Lin
Yvonne G
YG
Mangala
Lingegowda S
LS
Kim
Tae Jin
TJ
Coleman
Robert L
RL
Landen
Charles N
CN
Li
Yang
Y
Felix
Edward
E
Sanguino
Angela M
AM
Newman
Robert A
RA
Lloyd
Mary
M
Gershenson
David M
DM
Kundra
Vikas
V
Lopez-Berestein
Gabriel
G
Lutgendorf
Susan K
SK
Cole
Steven W
SW
Sood
Anil K
AK
D000818:Animals; D002277:Carcinoma / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007545:Isoproterenol / Q000819:agonists; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D009929:Organ Size; D010051:Ovarian Neoplasms / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology*; D010793:Phthalazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011859:Radiography; D011897:Random Allocation; D013315:Stress, Psychological; D013726:Terbutaline / Q000819:agonists; D014183:Transplantation, Heterologous; D047368:Tumor Burden; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
D004338:Drug Combinations; D004791:Enzyme Inhibitors; D010793:Phthalazines; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; C404768:vatalanib; D007545:Isoproterenol; D013726:Terbutaline