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M.-E. Jockovich, Y. Pina, H. Boutrid, T. G. Murray; Bone Marrow Derived Macrophages Are Present in Retinal Tumors from LHBETATAG Mice. Invest. Ophthalmol. Vis. Sci. 2008;49(13):76.
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© ARVO (1962-2015); The Authors (2016-present)
Macrophages are an integral part of the tumor microenvironment having both promoting and supporting roles in tumor growth and angiogenesis. The retina contains two types of macrophages: resident microglia and bone marrow derived. The purpose of this study is to analyze macrophage recruitment to retinal tumors using a mouse model of retinoblastoma.
This study was approved by the IACUC and follows ARVO guidelines. Sixteen week-old LHBETATAG mice (n=15) harboring large tumors were irradiated (950 cGy, single dose) to destroy their bone marrow (this dose of radiation does not affect retinal tumors). Bone marrow from T-cell depleted-age matched GFP-C57bl/6 were transplanted to ten irradiated LHBETATAG mice; five mice did not receive bone marrow transplant and served as controls. Blood components were allowed to reconstitute for 6 weeks at which time mice were euthanized by CO2 inhalation and their eyes enucleated for evaluation. Macrophages were identified by immunostaining with macrophage specific antibodies, Iba1 and F480.
Irradiated mice which did not receive bone marrow transplants survived three weeks post-irradiation. Conversely, chimeric mice survived until the experimental endpoint. Tumor size in chimeric mice comprised 40.3 % of the globe space. Tumors in untreated litter-matched controls comprised 54.5 % of the globe. This difference in tumor size is not statistically significant at this sample size. Macrophages constitute 2.7 (0.7) % of tumor area in these large tumors. GFP-positive bone marrow derived cells constitute 0.03 (0.05) % of the analyzed area. Results show that only 3.5 (5.6) % of the macrophage population in retinal tumors is GFP-positive, representing recruited macrophages.
We have previously shown that the number of tumor associated macrophages in LHBETATAG retinal tumors is directly proportional to tumor size. Both resident microglia and bone marrow derived macrophages have been implicated in traumatic, infectious and degenerative disorders of the central nervous system, including tumors. No marker is known to distinguish between resident microglia and blood derived macrophages. However, this knowledge may have profound implications for therapy. Results from this study suggest that a small fraction of macrophages in advanced retinal tumors harbored by this mouse model are bone marrow derived. These results indicate that a large component of tumor-associated macrophages is either activated microglia or circulating macrophages recruited early in disease progression.
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