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M.-E. Jockovich, J. Diaz-Caneja, Y. Pina, H. Boutrid, C. M. Cebulla, T. G. Murray; Role of Tumor Associated Macrophages in Retinoblastoma Tumor Growth. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1587.
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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 invasion, growth, angiogenesis, and metastasis. Macrophages support the developing tumor by expression of growth factors, chemokines and ECM remodeling enzymes. The objective of this study is to characterize the role of tumor associated macrophages in retinoblastoma tumor growth.
This study was approved by the IACUC and follows ARVO guidelines. LHBETATAG mice (n=6 per group) of 4, 8, 12 and 16 weeks of age were analyzed; These age groups represent pre-neoplastic, small, medium and large tumors respectively. Eyes were assessed by immunohistochemistry for the presence of macrophages (using the macrophage marker Iba-1). hypoxic cells using pimonidazole (a drug that specifically marks hypoxic cells and is detected by immunochemistry), vascular endothelial cells (labeled with a lectin from Griffonia simplicifolia), activated Müller cells (stained with cFOS), and MMP9, a critical molecule for retinoblastoma growth and also a potential product of macrophages.
Tumor associated macrophages are detected in small retinal tumors harbored by LHBETATAG mice; 1.3% of the tumor area in these small tumors is composed of macrophages. In medium size tumors there is a significant (p=0.0372) increase in the percentage of macrophages, 5.4%. This percentage decreases, not significantly, in advanced disease to 3.7 %. In LHBETATAG retinal tumors, a fraction of Iba-1-positive cells are tightly associated with the vasculature. A second group of positive cells are not associated with vessels but are found throughout the tumor, usually associated with activated Müller glia. Interestingly, macrophages do not co-localize to hypoxic tumor areas, suggesting that hypoxia is not a major mechanism of macrophage recruitment to retinal tumors. Our data also suggest that the gelatinase MMP9, which is essential for retinoblastoma growth, co-localizes with macrophages, suggesting that macrophages are responsible for a large fraction of MMP9 expression in these tumors.
In human retinoblastoma, macrophages often are localized adjacent to tumor vessels, usually embedded in the perivascular space. We postulate that the presence and position of these macrophages in LHBETATAG retinal tumors and in human retinoblastoma tumors are indicative of their vital role in this disease. Similar to other tumors, macrophages may play an important role in retinoblastoma progression. Consequently, anti-inflammatory agents may be a significant therapeutic target.
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