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Y. Pina, C. M. Cebulla, T. G. Murray, A. Alegret, S. Dubovy, H. Boutrid, W. Feuer, M.-E. Jockovich; Blood Vessel Maturation in Human Uveal Melanoma: Spatial Configuration of Endothelial Vessel Maturation and Neovasculature and Its Impact on Ocular Treatment. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4780.
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© ARVO (1962-2015); The Authors (2016-present)
To evaluate the spatial distribution of mature versus angiogenic vasculature in human uveal melanoma, as they may impact antiangiogenic therapies for the treatment of uveal melanoma.
This study was approved by the IRB of the University of Miami. Enucleated tumor-containing eyes (n=14) from patients with uveal melanoma were evaluated. Immunohistochemical analyses were performed to assess total (Lectin staining), angiogenic (endoglin staining), and mature vasculature (pericyte marker α-sma staining), and cellular proliferation (Ki67 staining). The spatial distribution of mature and angiogenic vasculature was analyzed for every tumor specimen by 3 independent raters, who showed excellent agreement (weighted kappa=0.83). Each tumor was examined for PAS patterns' distribution and tumor morphology (H&E staining).
Tumor vasculature is present throughout the tumor. Central areas of the tumors had higher mean gradings of endoglin (3.3±1.0) than α-sma (2.5±0.9, p=0.036). Endoglin gradings were greater for apical, left, and right areas, but not significantly so (p=0.17, 0.34, and 0.63, respectively); while basal gradings were greater for α-sma (3.4±1.6) than for endoglin (3.1±1.0), but not significantly so (p=0.47). We found extraocular tumor extension in one specimen characterized by mature vessels, while being negative for endoglin and Ki67. Ki67 co-localized to angiogenic areas and regions that delineated mature and angiogenic vascular areas. The prevalence of each PAS pattern was similar across locations, except for straight (1/14 apical vs. 5 to 7/14 at all other locations) and parallel (7/14 basal vs. 2/4 at all other locations). Averaged over all locations, α-sma gradings were borderline significantly correlated with tumor size (r=0.46, p=0.095), but endoglin gradings were not (r=0.11, p=0.72).
Significant differences exist in the spatial distribution of mature versus angiogenic vasculature in human malignant uveal melanoma. Blood vessel maturation may limit anti-angiogenic treatments that mainly target immature vasculature. Thus, the heterogeneity in melanoma vasculature is clinically significant, since it provides a rationale to give vascular targeting therapy and demonstrates why pure anti-angiogenic therapies may be limited. The development of future tumor treatment modalities such as pericyte targeting agents will provide a more comprehensive therapeutic approach for the treatment of uveal melanoma.
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