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Published on: December 2, 2022
Spontaneous uveal amelanotic melanoma in transgenic Tyr-RAS+ Ink4a/Arf-/- mice
William H Tolleson1, Jason C Doss, John Latendresse
1Division of Biochemical Toxicology, National Center for Toxicological Research, 3900 NCTR Road, Jefferson, AR 72079, USA. wtolleson@nctr.fda.gov
Objective:
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-RAS+ 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 microscopy. 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-RAS+ 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.
Insights
A new mouse model spontaneously develops uveal melanoma, mimicking human disease. This model aids research into the genetic causes of uveal melanoma.
Area of Science:
- Oncology
- Ophthalmology
- Genetics
Background:
- Uveal melanoma is a rare but aggressive eye cancer.
- Current research often relies on xenograft models, which may not fully replicate spontaneous tumor development.
- Understanding the genetic basis of uveal melanoma is crucial for developing effective treatments.
Purpose of the Study:
- To characterize a novel murine model of spontaneous amelanotic melanoma in the uvea.
- To evaluate the histopathological and ultrastructural features of these tumors.
- To assess the utility of this model for studying uveal melanoma.
Main Methods:
- Transgenic mice with a targeted deletion of Ink4a/Arf and expression of human H-ras under the tyrosinase promoter were used.
- Ocular lesions were monitored, and developed tumors were evaluated histologically and ultrastructurally.
- Immunohistochemistry was performed to detect specific markers (Melan-A, S100, neuron-specific enolase).
Main Results:
- Spontaneous uveal melanomas developed in 15.7% of mice within 6 months.
- Tumors were locally invasive but confined to the eye, without metastasis.
- Histopathology revealed epithelioid and spindle-shaped cells resembling human uveal melanoma, with positive staining for Melan-A, S100, and NSE.
Conclusions:
- This transgenic mouse model spontaneously develops uveal malignant melanomas with histopathological features similar to human uveal melanoma.
- The model arises in the choroid or ciliary body, offering insights into tumor origin.
- Engineered mouse models of spontaneous uveal melanoma are valuable for advancing research into the genetic underpinnings of this disease.
