Abstract
Retinoblastomas initiate in the developing retina in utero and are diagnosed during the first few years of life. We have recently generated a series of knockout mouse models of retinoblastoma that recapitulate the timing, location, and progression of human retinoblastoma. One of the most important benefits of these preclinical models is that we can study the earliest stages of tumor initiation and expansion. This is not possible in human retinoblastoma because tumors initiate in utero and are not diagnosed until they are at an advanced stage. We found that mouse retinoblastoma cells exhibit a surprising degree of differentiation, which has not been previously reported for any neural tumor. Early-stage mouse retinoblastoma cells express proteins found normally in retinal plexiform layers. They also extend neurites and form synapses. All of these features, which were characterized by immunostaining, Golgi-Cox staining, scanning electron microscopy, and transmission electron microscopy, suggest that mouse retinoblastoma cells resemble amacrine/horizontal cells from the retina. As late-stage retinoblastoma cells expand and invade the surrounding tissue, they lose their differentiated morphology and become indistinguishable from human retinoblastomas. Taken together, our data suggest that neuronal differentiation is a hallmark of early-stage retinoblastoma and is lost as cells become more aggressive and invasive. We also show that rosette formation is not a hallmark of retinoblastoma differentiation, as previously believed. Instead, rosette formation reflects extensive cell-cell contacts between retinoblastoma cells in both early-stage (differentiated) and late-stage (dedifferentiated) tumors.
Highlights
Mouse models of human cancer allow us to study early tumor formation and determine whether tumor cell differentiation is a hallmark of carcinogenesis
We recently found that amplification of the MDMX and MDM2 genes suppresses the p53 pathway in 75% of human retinoblastomas [9]
As in the mouse tumors, the human tumors contained a central plexus www.aacrjournals.org made up of large- and small-diameter processes, but we found no evidence for synaptic densities or synaptic vesicles in any of the seven human retinoblastomas analyzed by transmission electron microscopy (TEM)
Summary
Mouse models of human cancer allow us to study early tumor formation and determine whether tumor cell differentiation is a hallmark of carcinogenesis. These models must recapitulate the histopathologic and genetic features of the human disease. We and others have generated knockout mouse models of retinoblastoma by inactivating the Rb and p107 genes in the developing mouse retina of Chx10-Cre;RbLox/À;p107À/À mice [1,2,3,4]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Phone: 901-495-2257; Fax: 901-495-3143; E-mail: michael.dyer@ stjude.org. Doi:10.1158/0008-5472.CAN-06-3754 to retinoblastoma in mice [2] These mouse models are not the focus of this report, future analyses will compare data on the Rb;p107-deficient and Rb;p130-deficient retinoblastomas
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