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A. C. Schefler, Y. Pina, H. Boutrid, E. Hernandez, K. R. Padgett, L. Bajenaru, T. G. Murray; Anatomic, Histopathologic, and Gene Expression Analysis of Metastatic Tumors in the LhBetaTag Mouse Model of Retinoblastoma. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5708.
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The purpose of this study was to: 1) establish a non-invasive imaging protocol that could be used to document the growth of murine retinoblastoma and accurately estimate tumor size, and 2) characterize the metastatic disease that develops in this LHBetaTag transgenic model.
This study protocol was approved by the University of Miami institutional use and animal care committee (IACUC). LHBetaTag transgenic retinoblastoma mice who developed tumors by 16 weeks of age were evaluated. The anatomic location of the eye tumors and metastases was explored by performing magnetic resonance imaging (MRI) scans at 16, 20, 24, 27, and 30 weeks of age and comparing abnormally enlarged structures to scans performed on wild type mice. Eyes were enucleated at 20 weeks and were divided into 2 groups: a) those placed in OCT, snap frozen in liquid nitrogen, and sectioned, or b) those placed in Trizol, frozen, and used for microarray analysis. The metastatic disease sites were then followed serially by MRI in order to confirm the enlargement of the disease over time. Animals were euthanized at 32 weeks of age and metastases were harvested. Histopathologic analysis was performed on the metastatic tissue. Gene expression analysis by microarray was performed by isolating total RNA from the primary tumor and metastatic tissue.
A standard MRI sequence was established for the mice which focused on the head and neck region. This sequence was able to accurately detect small intraocular tumors as well as large ones and track their growth. Metastases were consistently identified by the age of 27 weeks in the parotid and salivary glands and were shown to increase in size with time. These sites were confirmed with histopathologic analysis. Gene expression analysis revealed a consistent difference in the profile of genes expressed in primary tumor tissue compared with metastatic disease.
Murine retinoblastoma displays a unique pattern of metastatic disease development with masses forming in the parotid and salivary glands by 27 weeks of age. A unique profile of gene expression is present in these metastatic sites compared to the primary tumor. These genomic changes present a possible molecular target for the treatment of metastatic human retinoblastoma.
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