Alphavbeta3 integrin antagonist S247 decreases colon cancer metastasis and angiogenesis and improves survival in mice.
Members of the integrin family influence several aspects of tumor progression and metastasis, including cell survival, proliferation, and angiogenesis. Specific integrins such as alpha(v)beta(3) and alpha(v)beta(5) are involved in regulating endothelial cell function, and thus angiogenesis. We evaluated the effect of the alpha(v)beta(3)/alpha(v)beta(5) integrin antagonist S247 on the growth and angiogenesis of colon cancer liver metastases in an orthotopic murine model. Murine colon cancer cells were injected into the spleens of BALB/c mice to produce liver metastases. On day 7, miniature osmotic pumps were implanted into the subcutis to continuously infuse either saline or 70 mg/kg/day S247. All mice were sacrificed when control mice became moribund. Mice that received S247 developed significantly fewer liver metastases than did controls (P < 0.05). Using the same model, a subsequent survival study was performed. Mice were sacrificed when moribund as determined by an observer blinded to the treatment given. Treatment with S247 significantly prolonged overall survival (P < 0.05). Interestingly, primary tumors in the spleen were the cause of death in the S247-treated group as S247 appeared to have little effect on these tumors. Immunohistochemical staining demonstrated a significant reduction of vessels in liver metastases of S247-treated mice (P < 0.001), a significant increase in endothelial cell apoptosis (P < 0.05), and a significant decrease in pericyte coverage (P < 0.0001). To determine the role of S247 on angiogenesis, we examined the effect of S247 in vitro on human umbilical vein endothelial cells (HUVECs) and human vascular smooth muscle cells (hVSMCs). The addition of S247 to HUVECs and hVSMCs growing on vitronectin-coated flasks and in Matrigel significantly impaired cell growth and colony formation, respectively (P < 0.05). Furthermore, S247 completely inhibited the attachment of HUVECs and hVSMCs and increased apoptosis by six- to 9fold compared with controls. In in vitro invasion assays, S247-treated cells demonstrated decreased migration (P < 0.05). In conclusion, S247 demonstrated significant antimetastatic and antiangiogenic activity and impaired both endothelial and hVSMC/pericyte function in vitro and in vivo. The use of agents such as integrin antagonists that target multiple cell types involved in angiogenesis may be a more effective method of inhibiting angiogenesis than agents targeting only the endothelial cells.
Reinmuth
Niels
N
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Liu
Wenbiao
W
Ahmad
Syed A
SA
Fan
Fan
F
Stoeltzing
Oliver
O
Parikh
Alexander A
AA
Bucana
Corazon D
CD
Gallick
Gary E
GE
Nickols
Maureen A
MA
Westlin
William F
WF
Ellis
Lee M
LM
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003110:Colonic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D008113:Liver Neoplasms / Q000517:prevention & control* / Q000556:secondary*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009930:Organic Chemicals / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D020533:Angiogenesis Inhibitors; D039302:Integrin alphaVbeta3; D009930:Organic Chemicals; C474314:S 247 compound