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Identification of a Novel Metastasis-suppressor Region on Human Chromosome 12¹

Departments of Surgery, Section of Urology [H. H. L., G. P. Z., Z. D., S. L. C., R. C. S., C. W. R-S.] and Medicine, Section of Hematology/Oncology [E. M. D., M. M. L.], University of Chicago, Chicago, Illinois; Department of Medical Microbiology/Immunology, Southern Illinois University School of Medicine, Springfield, Illinois [K. W.]; Department of Urology, Teikyo University School of Medicine, Ichihara Hospital, Ichihara-shi, Chiba 299-01, Japan [Y. I., T. I.]; and The Prostate Cancer Program, The University of Chicago Cancer Research Center, Chicago, Illinois 60637 [C. W. R-S.]

There is a critical need for markers that can be used to predict accurately the malignant potential of histological prostate cancers (J. T. Isaacs, Am. J. Pathol., 150: 1511–1521, 1997). Metastasis-suppressor genes are attractive candidates for marker development because, by definition, their loss should be associated with the acquisition of metastatic ability. In an effort to identify such genes, a single copy of human chromosome 12, tagged with the neomycin resistance gene, was introduced into highly metastatic Dunning AT6.1 prostate cancer cells by microcell-mediated chromosomal transfer. Thirty-two AT6.1-12 clonal cell lines were established and the region(s) of chromosome 12 retained was determined by sequence tagged site-based PCR analysis. Representative AT6.1-12 clones containing overlapping regions of chromosome 12 were characterized cytogenetically and were shown to have a normal complement of parental AT6.1 rat chromosomes. Fluorescence in situ hybridization, performed on representative AT6.1-12 hybrids, demonstrated a single human chromosome 12-specific signal. The metastatic ability of six representative clones was tested in immunodeficient mice. All of the AT6.1-12 clones showed the same in vivo growth rates as the control AT6.1-neo cells. Clonal cell lines that contained a conserved 70-cM portion of chromosome 12 (e.g., AT6.1-12-8, -8-1, and -8-3), showed a >30-fold suppression in the number of macroscopic surface lung metastases. Mice that received injections of these cells developed a mean number 4 lung metastases whereas mice that received injections of other AT6.1-12 hybrids (lacking the 70-cM region) or AT6.1-neo control cells, developed a mean number of 140 metastases. Interestingly, histological examination of the lungs of the mice that received injections of AT6.1-12-8 cells showed essentially no microscopic metastases. These findings suggest that a gene(s) encoded by the 70-cM portion of human chromosome 12 suppresses an early step in the metastatic cascade.

¹ This work was supported by University of Chicago Surgery Research Committee Grant; Cancer Research Foundation Young Investigator Award and NIH First Award R29 CA69487 02 (C. W. R-S.), Howard Hughes Medical Institute (H. H. L., C. W. R-S.), University of Chicago RESCUE Fund (C. W. R-S.), NIH PO1 CA40046 (M. M. L.), and Grants-in-aid 09470340 and 08265106 from the Ministry of Education, Science, Sports and Culture, Japan (T. I.).

² To whom requests for reprints should be addressed, at Section of Urology, Department of Surgery, 5841 South Maryland MC6038, Chicago, IL 60637. Phone: (773) 702-3132; Fax: (773) 702-1001; E-mail: crinker@surgery.bsd.uchicago.edu.

Received 4/27/98. Accepted 6/25/98.

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