Overcoming cellular senescence in human cancer pathogenesis
- Thomas R. Yeager1,6,
- Sandy DeVries10,
- David F. Jarrard1,4,5,
- Chinghai Kao9,
- Stephen Y. Nakada4,5,
- Timothy D. Moon4,5,
- Reginald Bruskewitz4,5,
- Walter M. Stadler8,
- Lorraine F. Meisner7,
- Kennedy W. Gilchrist3,5,
- Michael A. Newton2,
- Frederic M. Waldman10, and
- Catherine A. Reznikoff1,5,6,11
- Departments of 1Human Oncology, 2Biostatistics, 3Pathology, and 4Surgery, 5University of Wisconsin Comprehensive Cancer Center and University of Wisconsin Medical School, 6Program in Cellular and Molecular Biology, and 7State Laboratory of Hygiene, Madison, Wisconsin 53792 USA; 8Department of Hematology/Oncology, University of Chicago, Chicago, Illinois 60637 USA; 9Department of Urology, University of Virginia, Charlottesville, Virginia 22908 USA; 10Department of Laboratory Medicine and Division of Molecular Cytometry, University of California at San Francisco, San Francisco, California 94143 USA
Abstract
Elevation of p16, the CDKN2/p16 tumor suppressor gene (TSG) product, occurs at senescence in normal human uroepithelial cells (HUC). Immortal HUCs and bladder cancer cell lines show either alteration of p16 or pRb, the product of the retinoblastoma (RB) TSG. In addition, many human cancers show p16 or pRb alteration along with other genetic alterations that we associated with immortalization, including +20q and −3p. These observations led us to hypothesize that p16 elevation plays a critical role in senescence cell cycle arrest and that overcoming this block is an important step in tumorigenesis in vivo, as well as immortalization in vitro. Using a novel approach, we tested these hypotheses in the present study by examining p16 and pRb status in primary culture (P0) and after passage in vitro of transitional cell carcinoma (TCC) biopsies that represented both superficial bladder tumors and invasive bladder cancers. We demonstrated that all superficial TCCs showed elevated p16 after limited passage in vitro and then senesced, like normal HUCs. In contrast, all muscle invasive TCCs contained either a p16 or a pRb alteration at P0 and all spontaneously bypassed senescence (P = 0.001). Comparative genomic hybridization (CGH) was used to identify regions of chromosome loss or gain in all TCC samples. The application of a statistical model to the CGH data showed a high probability of elevated alteration rates of +20q11−q12 (0.99) and +8p22−pter (0.94) in the immortal muscle invasive TCCs, and of −9q (0.99) in the superficial TCCs. Three myoinvasive TCCs lost 3p13−p14. In this study, four of six myoinvasive TCCs also showedTP53 mutation that associated well with genome instability (P = 0.001), as previously hypothesized. Notably,TP53 mutation, which has been used as a marker of tumor progression in many human cancers, was less significant in associating with progression in this study (P = 0.04) than was p16 or pRb alteration (P = 0.001). Thus, these data support a new model in which overcoming senescence plays a critical role in human cancer pathogenesis and requires at least two genetic changes that occur in several combinations that can include either p16 or pRb loss and at least one additional alteration, such as +20q11−q12, −3p13−p14, or −8p21−pter.
Keywords
Footnotes
-
↵11 Corresponding author.
-
E-MAIL CRezniko{at}FACSTAFF.wisc.edu; FAX (608) 262-8430.
-
- Received September 10, 1997.
- Accepted November 11, 1997.
- Cold Spring Harbor Laboratory Press
