Transgenic Mouse Models for Tumors of Melanocytes and Retinal Pigment Epithelium

Abstract

Cutaneous and ocular melanomas are due to malignant transformation of neural crest-derived melanocytes. The rising incidence of this tumor in humans has stimulated experiments to devise suitable mouse models. In the past years, transgenic mouse lines have been generated using different oncogenes - Ha-ras, SV40 T antigen (Tag), ret - which develop benign lesions of melanocytes, melanoma, and/or eye tumors. Pigment cell tumors in humans, although rather rare, can also develop from the retinal pigment epithelium (RPE), a cell layer of neuroectodermal origin. We, therefore, established transgenic models for this ocular tumor. Regulated by the promoter of tyrosinase-related protein-1 (TRP-1), two oncogenes, ret and SV40 Tag, were targeted to the developing RPE in transgenic mice. The TRP-1/ret transgenic mice displayed microphthalmia and benign tumors of the RPE. Expression of SV40 T antigen (TRP-1/Tag) led to malignant tumors, which were invasive and metastasized to inguinal lymph node and spleen.

Transforming functions of Simian Virus 40

“…The role of the J domain has been less studied in transgenic models, and the reports so far indicate an important -although tissue-speci®c-dependency on the J domain to induce tumors (Chen et al, 1992;Ratineau et al, 2000;Symonds et al, 1993). In each of these cases, the amino-terminal fragment of LT is su cient to drive Fox et al, 1989;Zennaro et al, 1998;Le Menuet et al, 2000Bone Behringer et al, 1988Knowles et al, 1990;Jensen et al, 1993;Wilkie et al, 1994 Brain andnervous system Brinster et al, 1984;Reynolds et al, 1988;Chen et al, 1989;Theuring et al, 1990;Chen and Van Dyke, 1991;Perraud et al, 1992;Smith et al, 1992;Jensen et al, 1993;Chiu et al, 2000Cartilage Cheah et al, 1995Digestive system Li et al, 1995Kim et al, 1994;Hauft et al, 1992;Asa et al, 1996Eye Theuring et al, 1990Penna et al, 1998;Beermann et al, 1999Heart Behringer et al, 1988Kidney Theuring et al, 1990Liver Dyer and Messing, 1989Sandgren et al, 1989;Sepulveda et al, 1989;Butel et al, 1990;Manickan et al, 2001Lung Sandmoller et al, 1994Wikenheiser et al, 1992Lymphoid tissue Reynolds et al, 1988Chen et al, 1989Mammary...…”

Absence of fibroblast growth factor 2 does not prevent tumor formation originating from the RPE

“…This suggests that FGF2 could be implicated in melanocyte proliferation and melanoma formation. This hypothesis can be tested in future experiments using FGF2-de®cient mice and mouse models for melanoma (Beermann et al, 1999).…”

“…In addition, pigmented ocular tumors can develop from proliferating cells of the retinal pigment epithelium (Loe er et al, 1996). In melanoma mouse models, which have been produced using the tyrosinase promoter linked to SV40 transforming sequences, tumors in the RPE and choroid-RPE interphase have been observed (Anand et al, 1994;Beermann et al, 1999;Bradl et al, 1991;Mintz and Klein-Szanto, 1992). We recently used the promoter of the tyrosinaserelated protein 1 gene (Tyrp1) to target expression of SV40 T antigen (Tag) to the developing RPE .…”

Cutaneous melanoma in genetically modified animals

“…Over the past 15 yr, many attempts have been made to use transgenic approaches in the mouse to model melanoma (Beermann, 2006; Beermann et al., 1999; Chin et al., 2006; Kabbarah and Chin, 2006; Walker and Hayward, 2002) (Figure 4, Table 2).…”