The targeting of phosphoinositide-3 kinase attenuates pulmonary metastatic tumor growth following laparotomy.
OBJECTIVE
We aimed to characterize a potential role for phosphatidylinositol 3-kinase (PI3k) in leading to accelerated postoperative metastatic tumor growth.


BACKGROUND
PI3k enhances tumor cell survival in part by phosphorylating Akt and reducing apoptosis. Postoperatively, apoptosis is reduced within local recurrences and distant metastases. This reduction is associated with the phenomenon of accelerated postoperative tumor growth.


METHODS
Balb/c mice underwent a tail vein injection of 1x10 metastatic murine mammary adenocarcinoma 4T1 cells. Animals were divided into the following treatment groups (n=10/group): group A, controls; group B, DMSO intraperitoneally (IP) daily from days 14 to 21; group C, IP LY294002 daily from days 14 to 21; group D, laparotomy only; group E, laparotomy followed by IP DMSO for 7 days; and group F, laparotomy followed by LY294002 IP for 7 days. All laparotomies were performed on day 14. Animals were killed at day 28. Metastatic tumor burden was assessed using the lung/body weight ratio and a histologic metastatic index. Mitotic counts and apoptotic indices were established using a combination of hematoxylin and eosin histology and TUNEL immunohistochemistry. A parallel survival study was performed, and PI3k activity was assessed using western blots for phospho-Akt.


RESULTS
Laparotomy was associated with increased systemic tumor burden (P=0.001). Postoperatively, LY294002 significantly attenuated metastatic tumor growth (P<0.001). Effective PI3k inhibition was confirmed by demonstrating a reduced Akt phosphorylation. Moreover, PI3k inhibition led to reduced proliferation, increased apoptosis (P<0.001), and enhanced postoperative survival (P<0.001).


CONCLUSIONS
Targeting PI3k with postoperative LY294002 significantly attenuates the acceleration in postoperative metastatic tumor growth seen following laparotomy.
Coffey
J Calvin
JC
Department of Surgery, Cork University Hospital, University College Cork, Cork, Ireland. calvincoffey@hotmail.com
Wang
Jiang H
JH
Bouchier-Hayes
David
D
Cotter
Tom G
TG
Redmond
H Paul
HP
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology* / Q000601:surgery*; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002455:Cell Division; D002867:Chromones / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D007813:Laparotomy; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology* / Q000601:surgery*; D051379:Mice; D008807:Mice, Inbred BALB C; D009025:Morpholines / Q000494:pharmacology*; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology* / Q000601:surgery*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014407:Tumor Cells, Cultured
D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one