The TAg-RB Murine Retinoblastoma Cell of Origin Has Immunohistochemical Features of Differentiated Müller Glia with Progenitor Properties

Pajovic, Sanja; Corson, Timothy W.; Spencer, Clarellen; Dimaras, Helen; Orlic-Milacic, M; Marchong, Mellone N.; To, Kwong Him; Thériault, Brigitte L.; Auspitz, Mark; Gallie, Brenda L.

doi:10.1167/iovs.11-7989

Cited by 26 publications

(26 citation statements)

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“…4 Moreover, we have never observed overlap between TAg and cone opsin or RXR␥ staining (Pajovic S, unpublished data, 2010), but have shown overlap with multiple cell markers that clearly demonstrated that the cell of origin in this model possesses features of differentiated Müller glia with progenitor properties. 2 Although timing of pRB inactivation in our model makes it "not surprising that the cells stain for maturing progenitors," what is interesting is that inactivation of pRB at this time and in this unique cell type produces a tumor with significant similarity to human retinoblastoma, regardless of whether it originates from the same cell type.…”

Section: Madhavan and Khetanmentioning

confidence: 88%

“…2 First, we reiterate that it is not possible to draw direct conclusions about the cell of origin of human retinoblastoma on the basis of data in the TAg-RB mouse model; unfortunately, we lack the unambiguous marker of the tumor lineage in human retinoblastoma that TAg provides in the mouse. Second, the timing of RB1 loss in humans does not coincide with the developmental period in which TAg is activated in TAg-RB.…”

Section: Madhavan and Khetanmentioning

confidence: 97%

“…Human retinoblastoma tumors have frequently been detected prenatally. 3 TAg-RB arises from the inner nuclear layer after postnatal day 8, 2 and so it is unlikely to display a cone phenotype, as Madhavan and Khetan postulate, since the cones have already matured by that point. 4 Moreover, we have never observed overlap between TAg and cone opsin or RXR␥ staining (Pajovic S, unpublished data, 2010), but have shown overlap with multiple cell markers that clearly demonstrated that the cell of origin in this model possesses features of differentiated Müller glia with progenitor properties.…”

Section: Madhavan and Khetanmentioning

confidence: 99%

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Author Response: Does the Time of Inactivation of pRb Determine the Cell of Origin of Retinoblastoma?

Corson

Pajovic

Dimaras

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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raise questions about our paper that were largely addressed in the original publication.2 First, we reiterate that it is not possible to draw direct conclusions about the cell of origin of human retinoblastoma on the basis of data in the TAg-RB mouse model; unfortunately, we lack the unambiguous marker of the tumor lineage in human retinoblastoma that TAg provides in the mouse. Second, the timing of RB1 loss in humans does not coincide with the developmental period in which TAg is activated in TAg-RB. Human retinoblastoma tumors have frequently been detected prenatally. TAg-RB arises from the inner nuclear layer after postnatal day 8, 2 and so it is unlikely to display a cone phenotype, as Madhavan and Khetan postulate, since the cones have already matured by that point. 4 Moreover, we have never observed overlap between TAg and cone opsin or RXR␥ staining (Pajovic S, unpublished data, 2010), but have shown overlap with multiple cell markers that clearly demonstrated that the cell of origin in this model possesses features of differentiated Müller glia with progenitor properties.2 Although timing of pRB inactivation in our model makes it "not surprising that the cells stain for maturing progenitors," what is interesting is that inactivation of pRB at this time and in this unique cell type produces a tumor with significant similarity to human retinoblastoma, regardless of whether it originates from the same cell type.We agree with Madhavan and Khetan 1 that the genetic changes after Rb1 loss should be evaluated in other mouse models of retinoblastoma, and we would welcome such studies. Indeed, we regard our original paper as an invitation to our colleagues to molecularly and histologically define other mouse models and to interpret mouse data with caution in regard to human retinoblastoma. However, the assertion that the TAg-RB model cannot be considered to be a "good" model for human disease without such studies 1 is flawed. It has been said that there are no good models, only useful ones.5 Despite a different initiating mechanism and cell of origin, our data indicate histologic and (post-RB1 loss) molecular similarities between TAg-RB and human retinoblastoma. These similarities, plus the recent successful translation of therapies tested in TAg-RB to the clinic, 6,7 validate TAg-RB as a useful model. After more than 30 years of research, the identity of the retinoblastoma cell of origin remains complex and invites discussion; but most of all, it requires far more research in both mouse models and human disease.

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Section: Madhavan and Khetanmentioning

confidence: 88%

Section: Madhavan and Khetanmentioning

confidence: 97%

Section: Madhavan and Khetanmentioning

confidence: 99%

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Author Response: Does the Time of Inactivation of pRb Determine the Cell of Origin of Retinoblastoma?

Corson

Pajovic

Dimaras

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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“…The early stages of tumor development in the Tag model were investigated by Pajovic et al [7] by tracking Tag protein expression in the retina. The SV40 Tag causes neoplastic transformation of the developing retinal cells.…”

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confidence: 99%

Transgenic Models in Retinoblastoma Research

Nair

Vemuganti

2015

Ocul Oncol Pathol

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Understanding the mechanism of retinoblastoma (Rb) tumor initiation, development, progression and metastasis in vivo mandates the use of animal models that mimic this intraocular tumor in its genetic, anatomic, histologic and ultrastructural features. An early setback for developing mouse Rb models was that Rb mutations did not cause tumorigenesis in murine retinas. Subsequently, the discovery that the p107 protein takes over the role of pRb in mice led to the development of several animal models that phenotypically and histologically resemble the human form. This paper summarizes the transgenic models that have been developed over the last three decades. . The SV40 genome has several oncogenes in both the large T and the small t region which are predicted to cause a neoplastic transformation of the tissues by binding to p53, the pRB family and phosphatase pp2A proteins [2] . The murine eye tumors showed the histological characteristics of human Rb, including the presence of the neuronal marker NSE and synaptophysin

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“…We read with interest a recent paper by Pajovic et al, 1 on the TAg-RB murine retinoblastoma cell of origin. We would like the authors to answer a few queries that may help us to understand the work better.…”

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Does the Time of Inactivation of pRb Determine the Cell of Origin of Retinoblastoma?

Madhavan

Khetan

2011

Invest. Ophthalmol. Vis. Sci.

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We read with interest a recent paper by Pajovic et al., 1 on the TAg-RB murine retinoblastoma cell of origin. We would like the authors to answer a few queries that may help us to understand the work better. The expression of TAg was first observed in the nuclei of sparse cells within the inner nuclear layer at P8, the period during which Müller and bipolar cells are generated. When we look at the retinal cell lineage, the other retinal cells including the cone photoreceptors would have undergone differentiation by that period.2 As retinal cells strictly follow the competence model for retinal development, 3 Müller cells and bipolar cells are generated between postnatal day P4 and P6.2 So, it is not surprising that the cells stain for maturing progenitors like Müller and bipolar cells.Xu et al. 4 reported human retinoblastoma to have properties of a cone precursor. If P8 is the period during which pRB and p53 are inactivated by the transgene in TAg-RB murine retinoblastoma model, the equivalent period in the human fetus would be 19 weeks, 2 the stage at which ganglion cells and cone photoreceptors would have already evolved. Could it be that, in human retinoblastoma, the timing of pRB inactivation is much earlier-that is, during the stage at which the cones evolve? Using cone precursor markers such as CRX, RXR␥, and TR␤ 2 to stain the mouse tumor might be useful in identifying the cone cell status in this model. Further, as the authors rightly pointed out, the genetic changes after RB1 loss have to be evaluated in the other murine retinoblastoma models before concluding that the TAg-RB murine retinoblastoma model is a good one for the study of therapies for human retinoblastoma.Jagadeesan Madhavan,

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The TAg-RB Murine Retinoblastoma Cell of Origin Has Immunohistochemical Features of Differentiated Müller Glia with Progenitor Properties

Abstract: TAg-RB tumors displayed molecular similarity to human retinoblastoma and origin in a cell with features of differentiated Müller glia with progenitor properties.

Cited by 26 publications

References 56 publications

Author Response: Does the Time of Inactivation of pRb Determine the Cell of Origin of Retinoblastoma?

Author Response: Does the Time of Inactivation of pRb Determine the Cell of Origin of Retinoblastoma?

Transgenic Models in Retinoblastoma Research

Does the Time of Inactivation of pRb Determine the Cell of Origin of Retinoblastoma?

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