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Metastasizing Neuroblastomas in Mice Transgenic for Simian Virus 40 Large T (SV40T) under the Olfactory Marker Protein Gene Promoter¹

Department of Immunology, The Scripps Research Institute, La Jolla, California 92037

The olfactory marker protein (OMP) is a M_r 19,000 polypeptide originally considered a selective marker for differentiated olfactory receptor neurons. In an attempt to induce neoplastic proliferation in the olfactory cells, we made mice transgenic for the simian virus 40 large T-antigen gene linked to the OMP gene promoter. Four independent lines of transgenic mice were established. Despite a high expression of the transgene in the olfactory receptor neurons, no evidence of tumor growth was observed. Instead, starting from an age of 4 months, animals of all four lines presented with highly metastatic tumors originating in the adrenal medullas or sympathetic ganglia. The histological, ultrastructural, and immunohistochemical features of the tumors were identical to those of human infant neuroblastoma. Five independent neuroblastoma cell lines were established from tumors of different transgenic animals. All cell lines constitutively express the endogeneous OMP gene. The transgene product, simian virus 40 large T-antigen, associates with the product of the anti-oncogene p53 in these cell lines. This transgene system not only offers a biologically faithful model for investigations on the pathogenesis of neuroblastoma, the most common solid neoplasia of infancy, it also raises intriguing questions about the role of the OMP gene for the differentiation of the sympathetic neurons.

¹ This work was funded by grants from the Swedish Cancer Society (1817), Swedish Medical Research Council (08879/09468), John and Augusta Persson foundation (JAP 1989/126, 1990/133, 1991/92, and 1992/106), GA&E Nilsson foundation, the Medical Faculty, Lund University (to B. S.), and The Academy of Finland (to L. C. A.).

² To whom requests for reprints should be addressed, at Department of Medical Molecular Biology, The Wallenberg Laboratory, University of Lund, Box 7031, S-220 07 Lund, Sweden.

³ Current address: Baxter Healthcare Corp., 3015 S. Daimler St., Santa Ana, CA 92705.

⁴ Current address: Department of Pathology, University of Helsinki, Haartmaninkatu 3, FIN-00250 Helsinki, Finland.

Received 3/16/94. Accepted 7/29/94.

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