Spontaneous uveal amelanotic melanoma in transgenic Tyr-RAS+ Ink4a/Arf-/- mice.
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.


CONCLUSIONS
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.


CONCLUSIONS
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.
Tolleson
William H
WH
Division of Biochemical Toxicology, National Center for Toxicological Research, 3900 NCTR Road, Jefferson, AR 72079, USA. wtolleson@nctr.fda.gov
Doss
Jason C
JC
Latendresse
John
J
Warbritton
Alan R
AR
Melchior
William B
WB
Chin
Lynda
L
Dubielzig
Richard R
RR
Albert
Daniel M
DM
D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D004195:Disease Models, Animal; D017353:Gene Deletion; D011905:Genes, ras / Q000235:genetics*; D005838:Genotype; D008297:Male; D018328:Melanoma, Amelanotic / Q000737:chemistry / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D014442:Monophenol Monooxygenase / Q000235:genetics*; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*; D014604:Uveal Neoplasms / Q000737:chemistry / Q000235:genetics / Q000473:pathology*
D014408:Biomarkers, Tumor; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF; D014442:Monophenol Monooxygenase