Spontaneous Uveal Amelanotic Melanoma in Transgenic Tyr-RAS+ Ink4a/Arf−/− Mice

Abstract

To characterize a murine model of spontaneous amelanotic melanoma arising in the uvea of transgenic mice bearing a targeted deletion of the Ink4a/Arf tumor suppressor locus (exons 2 and 3) and expressing human H-ras controlled by the human tyrosinase promoter. Methods: Ocular lesions developed in 20 (15.7%) of 127 male albino Tyr-RASϩ Ink4a/Arf−/− transgenic FVB/N mice within 6 months, and were evaluated histologically and ultrastructurally. Results: Uveal melanomas were locally invasive but confined to the eye, with no evidence of metastasis. Tumor cells exhibited epithelioid and spindle-shaped morphological features and closely resembled the human counterpart. Melan-A, S100 and neuron-specific enolase expression were detected immunohistochemically. Melanosomal structures were detected using electron mi-croscopy. The retinal pigment epithelium was intact above small melanomas, and electron microscopy of the tumors failed to show the presence of basement membrane formation or desmosomes. Conclusion: Spontaneous uveal malignant melanomas occurring in male Tyr-RASϩ Ink4a/Arf−/− transgenic mice arise within the choroid or ciliary body and share histopathological features characteristic of human uveal melanoma. Clinical Relevance: Uveal melanoma research has benefited from xenograft models, but engineered mouse models of spontaneous uveal amelanotic melanoma will undoubtedly further our understanding of the genetic underpinning for this disease.

Characterization of melanocyte‐specific inducible Cre recombinase transgenic mice

“…Although no evidence of recombination was detected in eye, including the uveal tract or retinal pigmented epithelium (Fig. 2h), a similar transgene construct driving expression of oncogenic Hras has induced ocular melanomas arising within the uveal tract (Tolleson et al, 2005).…”

A Mouse Model of Breast Cancer Metastasis to the Choroid of the Eye

“…To our knowledge, this is the first description of an animal model of this disease. A mouse model of malignant lymphoma metastasis to the eye has been reported previously [13], and uveal melanoma develops in transgenic mice expressing different oncogenes under the control of the tyrosinase promoter [14,15]. However, lymphoma and melanoma are very different diseases from breast cancer, so the metastases described here are a unique model of this complication of breast cancer.…”

In-vivo xenograft murine human uveal melanoma model develops hepatic micrometastases

“…The disadvantages of these models are irrelevant host infiltrate and tumor microenvironment and abundance of false-positive responses with drugs [9]. Another mouse uveal melanoma model recently reported is transgenic Tyr-RAS + Ink4α/Arf−/− mice with spontaneous uveal amelanotic melanoma [27]. In transgenic mice, early tumor formation events can be followed.…”