Surgical stress promotes tumor growth in ovarian carcinoma.
OBJECTIVE
Surgical stress has been suggested to facilitate the growth of preexisting micrometastases as well as small residual tumor postoperatively. The purpose of this study was to examine the effects of surgical stress on ovarian cancer growth and to determine underlying mechanisms responsible for increased growth.


METHODS
To mimic the effects of surgery, we did a laparotomy or mastectomy under isoflurane inhalation on athymic nude mice 4 days after i.p. tumor cell injection. Propranolol infusion via Alzet pumps was used to block the influence of sympathetic nervous system activation by surgical stress.


RESULTS
In both HeyA8 and SKOV3ip1 models, the mice in the laparotomy and mastectomy groups had significantly greater tumor weight (P < 0.05) and nodules (P < 0.05) compared with anesthesia only controls. There was no increase in tumor weight following surgery in the beta-adrenergic receptor-negative RMG-II model. Propranolol completely blocked the effects of surgical stress on tumor growth, indicating a critical role for beta-adrenergic receptor signaling in mediating the effects of surgical stress on tumor growth. In the HeyA8 and SKOV3ip1 models, surgery significantly increased microvessel density (CD31) and vascular endothelial growth factor expression, which were blocked by propranolol treatment.


CONCLUSIONS
These results indicate that surgical stress could enhance tumor growth and angiogenesis, and beta-blockade might be effective in preventing such effects.
Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Jeong-Won
JW
Lee
Mian M K
MM
Shahzad
Yvonne G
YG
Lin
Guillermo
G
Armaiz-Pena
Lingegowda S
LS
Mangala
Hee-Dong
HD
Han
Hye-Sun
HS
Kim
Eun Ji
EJ
Nam
Nicholas B
NB
Jennings
Jyotsnabaran
J
Halder
Alpa M
AM
Nick
Rebecca L
RL
Stone
Chunhua
C
Lu
Susan K
SK
Lutgendorf
Steve W
SW
Cole
Anna E
AE
Lokshin
Anil K
AK
Sood
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology* / Q000601:surgery*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000097:blood; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D055806:Microvessels / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000473:pathology; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000601:surgery*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011433:Propranolol / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism; D013315:Stress, Psychological / Q000473:pathology*; D014183:Transplantation, Heterologous / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism
D000319:Adrenergic beta-Antagonists; D016207:Cytokines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018809:Proliferating Cell Nuclear Antigen; D011943:Receptors, Adrenergic, beta; D042461:Vascular Endothelial Growth Factor A; D011433:Propranolol