Transgenic mice with pigmented intraocular tumors: tissue of origin and treatment.
OBJECTIVE
To describe the cell of origin, tumor progression, light and electron microscopic appearance, immunohistochemical properties, and response to frequently used anticancer therapies in two transgenic models of intraocular melanoma.


METHODS
Two lines of transgenic mice that develop pigmented intraocular tumors were produced with the SV40 T and t antigens under the control of the mouse tyrosinase gene. Tumors were sequentially studied and characterized by light microscopy, electron microscopy, and immunohistochemistry stains. Tumor response to two cycles of dacarbazine was assessed on the basis of tumor size in one group of animals. Response to external beam irradiation was measured by survival time in other animals.


RESULTS
Two lines of transgenic mice developed bilateral intraocular tumors with complete penetrance and without primary cutaneous melanomas. Tumors developed first in the retinal pigment epithelial layer, with subsequent retinal and choroidal invasion, extraocular extension, and metastasis. Tumors stained positive for S-100, HMB-45, and Fas-ligand. Electron microscopy revealed polarization of tumor cells with basement membrane formation, microvilli, immature melanosomes, and abundant endoplasmic reticulum. Dacarbazine significantly reduced tumor size in these mice, and a trend toward dose-dependent decrease in survival was found with external beam irradiation.


CONCLUSIONS
Tumors developed from the retinal pigment epithelium. Their histology and growth, however, closely resembled that of human choroidal melanoma. This model may be a useful tool for future studies of endogenous primary pigmented tumors limited to the eye. Response to standard therapies suggests it can serve as a model with which to evaluate therapeutic modalities.
Syed
N A
NA
Department of Ophthalmology, University of Pennsylvania, Philadelphia, USA.
Windle
J J
JJ
Darjatmoko
S R
SR
Lokken
J M
JM
Steeves
R A
RA
Chappell
R
R
Wallow
I H
IH
Koop
B A
BA
Mangold
G
G
Howes
K A
KA
Albert
D M
DM
D000818:Animals; D000951:Antigens, Neoplasm; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism; D003606:Dacarbazine / Q000494:pharmacology; D053222:Fas Ligand Protein; D005260:Female; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008545:Melanoma / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D058950:Melanoma-Specific Antigens; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000378:metabolism; D010857:Pigment Epithelium of Eye / Q000648:ultrastructure; D009418:S100 Proteins / Q000378:metabolism; D014604:Uveal Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000628:therapy
D000951:Antigens, Neoplasm; D000952:Antigens, Polyomavirus Transforming; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D058950:Melanoma-Specific Antigens; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D009418:S100 Proteins; D003606:Dacarbazine