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T. G. Murray, C. M. Cebulla, A. Alegret, Y. Pina, H. Boutrid, M.-E. Jockovich; Targeting the Tumor Microenvironment as a Therapeutic Strategy for Retinoblastoma. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1585.
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The tumor microenvironment provides functional and structural support to tumor cells. In order to test the role of tumor microenvironment in retinoblastoma tumor development, we investigated the components of the tumor microenvironment and how these components change during tumorigenesis in a transgenic model of retinoblastoma and in human retinoblastoma tissue samples.
This study was approved the IACUC (and follows ARVO guidelines for the use of animals in research) and by the IRB. To evaluate differences in microenvironment immunohistochemical analysis of 4 wk old (pre-neoplastic retinas) or 16 week old (advanced disease) LHBETATAG mice (n=6 per group), and human retinoblastoma tumor samples (Reese-EllsworthV; n=10) were performed.
At 4 weeks of age, LHBETATAG positive mice have significantly higher concentrations of angiogenic vessels in the inner nuclear layer (where tumors form) than wild-type controls (p=0.029), while the total blood vessel density in this area is not significantly different (p=0.86). Further analysis of retinas from these young mice suggests that a myriad of important candidate factors involved in angiogenesis, namely, MMP9, cFOS, VEGFR2 are upregulated in the vicinity of proliferating cells, denoted by ki67 staining, compared with non-proliferating areas of the transgenic retina and wild-type littermate controls. We see an increased complexity of the tumor microenvironment in LHBETATAG advanced retinal tumors e.g., macrophages, activated Müller cells, and perycites. Similar stromal components are detected in human retinoblastoma tumor samples.
Results from this study will inform clinicians on the optimal treatment strategies for this disease. We see that the angiogenic switch occurs in preneoplastic stages of tumor development. This unveils the possibility of prophylactic treatment for children with rb1 germ line mutations. Furthermore, we have seen that all advanced human retinoblastoma tumor samples tested have similar stromal components. Taken together, these data suggest that treatment strategies should consider focusing on components of the tumor stroma. A comprehensive approach targeting multiple components of the tumor microenvironment will result in more effective treatment strategies for this disease.
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