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Early Invasiveness Characterizes Metastatic Carcinoid Tumors in Transgenic Mice¹

Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724 [S. G. N. G., D. H., V. L. B.], and Department of Pathology, New York University Medical Center, New York, New York 10016 [I. S.]

The conversion of a normal cell into a metastatic tumor is thought to occur in a stepwise progression of genetic changes that affect both growth control and interactions with the extracellular environment. The development of invasiveness allows tumor cells to escape from their primary site. We have investigated transgenic mice that develop both invasive intestinal neuroendocrine tumors and noninvasive tumors of the pancreatic ß-cells. Visual inspection and gene expression studies indicate that the ß-cell tumors rarely metastasize. In contrast, intestinal tumors that first appear in submucosal areas metastasize with high frequency to the lymph nodes and liver. No evidence of preneoplastic mucosal lesions was seen in the intestine, indicating that invasiveness is acquired early in the tumorigenic progression of these cells. Comparison of intestinal and pancreatic neuroendocrine tumors in transgenic mice suggests that an early requirement for invasiveness may contribute to metastatic potential.

¹ This research was funded by grants from the National Cancer Institute (D. H.), the Greenwall Foundation (V. L. B.), and Monsanto Co. (Cold Spring Harbor Laboratory). V. L. B. was supported by a fellowship from the New York State Health Research Council (D4-027), and S. G. N. G. was supported by a Juvenile Diabetes Foundation Postdoctoral Fellowship.

² Present address: Howard Hughes Medical Institute, Center for Neurobiology and Behavior, Columbia University, New York, NY 10032.

³ Present address: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143.

⁴ Present address: Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599. To whom requests for reprints should be addressed.

Received 2/22/91. Accepted 6/28/91.

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