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M.E. Jockovich, Y. Pina, F. Suarez, E. Hernandez, T.G. Murray; Blood Vessel Heterogeneity in Retinal Tumors From LHBETATAG Mice Limits Vessel Targeting Therapy . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2833.
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© ARVO (1962-2015); The Authors (2016-present)
The purpose of this study is to evaluate blood vessel maturation in the LHBETATAG mouse model of retinoblastoma and to determine if vessel heterogeneity affects vascular targeting therapy in this same model system. Vessel heterogeneity was also analyzed in human retinoblastoma samples to assess the therapeutic potential of vessel targeting for this pediatric malignancy.
All experiments in this study were conducted in accordance with ARVO guidelines. Vessel heterogeneity in retinal tumors from LHBETATAG mice of 4, 8 12 and 16 weeks of age (n=8 per group) and human retinoblastoma samples (n=8) was assessed by immunofluorescence. Total blood vessels were detected by immunostaining with lectin from bandeira simplicifolia, novel vasculature with CD105 (endoglin) and pericyte–committed mature vessels with α–smooth muscle actin. Vessel targeting efficacy was assessed by treating 12 week–old mice with a sunconjunctival injection of the vessel targeting agent Combretastatin A4P (1mg/20µl). Eyes were analyzed at 1 day and 1 week post injection. Functional vessels were assessed by perfusion with Hoechst stain and vessel maturation was determined using the immunostaining techniques described above.
Vessel heterogeneity is detected in large tumors harbored by LHBETATAG mice. Novel vasculature is detected early in tumor formation and the fraction of novel vessels to total vessels decreases in larger tumors at 16 weeks of age. Vessel maturation, as measured by pericyte–commitment, is detected in large tumors concomitant with a decrease in novel vasculature. Mature vessels are resistant to vessel targeting by Combretastatin A4P in these mice. Pericyte commited, mature vessels, are detected in human retinoblastoma tumor samples.
Vessel heterogeneity is detected in retinal tumors of LHBETATAG mice. Mature vessels in LHBETATAG retinal tumors do not respond to vessel targeting therapy, remaining functional following treatment. Mature, pericyte–committed vessels, are detected in human retinoblastoma tumors. Taken together these results imply that vessel maturation may limit the efficacy of vessel targeting therapy in these solid tumors. These results support the role of vessel targeting as adjuvant to other therapeutic strategies.
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