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Model Organisms

Mice Expressing SV40 T Antigen Directed by the Intestinal Trefoil Factor Promoter Develop Tumors Resembling Human Small Cell Carcinoma of the Colon¹

¹ Department of Veterans Affairs Medical Center, San Francisco, California; Departments of ² Anatomy, ³ Pathology, and ⁴ Medicine, School of Medicine, University of California, San Francisco, California; and ⁵ Department of Medical Pathology and Center for Comparative Medicine, University of California, Davis, California

Requests for reprints: James R. Gum Jr., GI Research Laboratory (151M2), Department of Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121. Phone: 415-750-2095; Fax: 415-750-6972. E-mail: jgum{at}maelstrom.ucsf.edu

The colonic epithelium contains three major types of mature cells, namely, absorptive, goblet, and enteroendocrine cells. These cells are maintained by a complex process of cell renewal involving progenitor and stem cells, and colon cancers develop when this process goes awry. Much is known about the genetic and epigenetic changes that occur in cancer; however, little is known as to the specific cell types involved in carcinogenesis. In this study, we expressed the SV40 Tag oncogene in the intestinal epithelium under the control of an intestinal trefoil factor (ITF) promoter. This caused tumor formation in the proximal colon with remarkable efficiency. ITFTag tumors were rapidly growing, multifocal, and invasive. ITFTag tumor cells express synaptophysin and contain dense core secretory granules, markers of neuroendocrine differentiation. The cell type involved in the early steps of ITFTag tumorigenesis was studied by examining partially transformed crypts that contained populations of both normal and dysplastic cells. The dysplastic cell population always expressed both Tag and synaptophysin. Cells expressing Tag alone were never observed; however, normal enteroendocrine cells expressing synaptophysin but not Tag were readily visualized. This suggests that ITFTag tumor cells originate from the enteroendocrine cell lineage following a transforming event that results in Tag expression. ITFTag tumors closely resemble human small cell carcinomas of the colon, suggesting the possibility that these tumors might be derived from the enteroendocrine cell lineage as well.

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