Retinoblastoma tumor vessel maturation impacts efficacy of vessel targeting in the LH(BETA)T(AG) mouse model.
OBJECTIVE
The aim of this study was to quantify tumor cell proliferation and growth, analyze tumor blood vessel development, and determine the efficacy of antiangiogenic and angiostatic therapy in targeting mature vessels in retinal tumors of the LH(BETA)T(AG) mouse model for retinoblastoma.


METHODS
LH(BETA)T(AG) mouse retinas were analyzed at 4, 8, 12, and 16 weeks of age. Tumor burden was analyzed by histology; cell proliferation, vessel density, angiogenesis, and vessel maturation were detected by immunofluorescence. To assess the efficacy of mature vessel targeting, 16-week-old mice were treated with single subconjunctival injections of the selective vascular-targeting drug combretastatin A4 prodrug (CA4P) or anecortave acetate, and eyes were analyzed 1 day and 1 week after injection to determine microvessel density and the number of angiogenic and mature vessels.


RESULTS
Increased cell proliferation and angiogenesis were detected in the retinal inner nuclear layer (INL) before morphologic neoplastic changes were evident. As tumor size increased, angiogenesis diminished concomitantly with the appearance of mature vessels. Treatment with CA4P and anecortave acetate resulted in significant reductions in total vessel density. However, neither drug reduced the amount of alpha-smooth muscle actin (SMA)-positive, mature vessels.


CONCLUSIONS
Results of this study provide new insight into the relationship between tumor growth and blood vessel development in the LH(BETA)T(AG) mouse and establish the framework for defining the selective action of two vessel-targeting drugs against new blood vessels compared with mature blood vessels. These findings suggest a high potential value in targeting the process of angiogenesis in the treatment of children with retinoblastoma.
Jockovich
Maria-Elena
ME
Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida 33101, USA.
Bajenaru
M Livia
ML
Piña
Yolanda
Y
Suarez
Fernando
F
Feuer
William
W
Fini
M Elizabeth
ME
Murray
Timothy G
TG
D000199:Actins / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D001632:Bibenzyls / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D049109:Cell Proliferation; D004195:Disease Models, Animal; D000071063:Endoglin; D004730:Endothelium, Vascular / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D020286:Pericytes / Q000378:metabolism; D011244:Pregnadienediols / Q000627:therapeutic use; D019572:Retinal Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D012175:Retinoblastoma / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D013267:Stilbenes / Q000627:therapeutic use
D000199:Actins; D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D001632:Bibenzyls; D014408:Biomarkers, Tumor; D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D019394:Ki-67 Antigen; D011244:Pregnadienediols; D013267:Stilbenes; C040105:combretastatin; C418047:anecortave acetate