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A. J. Johnson, E. Aguilar, V. Marchetti, M. Wang, F. Barnett, M. Friedlander; Bone Marrow-Derived Progenitor Cells Target to Melanoma Tumors and Reduce the Capacity of Melanin Production in a Murine Model of Melanoma. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4280.
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© ARVO (1962-2015); The Authors (2016-present)
We have previously described preferential targeting of adult bone marrow-derived lineage negative (Lin-) cells and myeloid progenitor cells (CD44Hi) to developing and hypoxia-induced neovasculature in the mouse retina and glioblastomas in rodent brains. We wanted to determine if (1) these cells also target to sites of tumor-associated vasculature in a murine model of ocular melanoma and (2) whether these cells can reduce the growth and size of ocular melanoma tumors as well.
Murine melanoma B16F10 cells or human uveal melanoma Mel290 cells were sub-retinally injected into 11-13 week old Balb/C, albino Black6 or athymic nude mice at varying concentrations on Day 0. On Day 7, varying concentrations of CD44Hi cells from GFP transgenic mice were subretinally injected and the mice sacrificed at Day 14. Eyes were enucleated, fixed, frozen and embedded in OCT. Frozen sections were either stained with H&E to visualize morphology or treated with DAPI to visualize nuclei and examined by indirect immunofluorescence in a scanning laser confocal microscope.
Five days after injection multiple dense nucleated regions in close proximity to each other were observed in the sub-retinal space. By Day 12 the nucleated regions had increased to a median size of approximately 4-6 disc diameters. GFP-positive cells, typically either rounded or ramified, were observed randomly distributed throughout the tumor. Ramified cells were observed in close proximity to vessels closely approximated to, or wrapped around, individual cells of the tumor. In addition, eyes treated with CD44Hi cells had a 50% reduction in size of the tumors and an 80% reduction in the incidence of melanotic tumors. Microscopic analysis of these eyes showed large areas of tumor necrosis whereas eyes that did not receive CD44Hi cells had large tumors. An in vitro apoptosis assay demonstrated tumor cells plated with CD44Hi cells had a 70% reduction in viability compared to control plates of tumor cells only.
Histologic examination of murine eyes injected with GFP-expressing CD44Hi cells showed that these progenitor cells preferentially target to sites of implanted murine and human ocular melanoma in vivo. Progenitor cells may be activated by tumor-associated signals, causing apoptosis of tumor cells both in vitro and in vivo. The activity of these cells may be increased by transfection with plasmids encoding angiostatic, and other anti-tumor molecules and may be useful as a form of cell-based therapy for treating vascular tumors of the eye and CNS.
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