Overcoming cellular senescence in human cancer pathogenesis

Thomas R. Yeager, Sandy DeVries, David F. Jarrard, Chinghai Kao, Stephen Y. Nakada, Timothy D. Moon, Reginald Bruskewitz, Walter M. Stadler, Lorraine F. Meisner, Kennedy W. Gilchrist, Michael A. Newton, Frederic M. Waldman, Catherine A. Reznikoff

Research output: Contribution to journalArticle

119 Citations (Scopus)

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 showed TP53 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.

Original languageEnglish (US)
Pages (from-to)163-174
Number of pages12
JournalGenes and Development
Volume12
Issue number2
StatePublished - Jan 15 1998
Externally publishedYes

Fingerprint

Cell Aging
Urinary Bladder Neoplasms
Comparative Genomic Hybridization
Transitional Cell Carcinoma
Tumor Suppressor Genes
Neoplasms
Muscles
Mutation
Retinoblastoma
Genomic Instability
Statistical Models
Tumor Biomarkers
Cell Cycle Checkpoints
Carcinogenesis
Chromosomes
Biopsy
Cell Line
In Vitro Techniques

Keywords

  • +20
  • -3p
  • -8p
  • Cancer progression
  • p16
  • p53
  • pRb
  • Senescence

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Yeager, T. R., DeVries, S., Jarrard, D. F., Kao, C., Nakada, S. Y., Moon, T. D., ... Reznikoff, C. A. (1998). Overcoming cellular senescence in human cancer pathogenesis. Genes and Development, 12(2), 163-174.

Overcoming cellular senescence in human cancer pathogenesis. / Yeager, Thomas R.; DeVries, Sandy; Jarrard, David F.; Kao, Chinghai; Nakada, Stephen Y.; Moon, Timothy D.; Bruskewitz, Reginald; Stadler, Walter M.; Meisner, Lorraine F.; Gilchrist, Kennedy W.; Newton, Michael A.; Waldman, Frederic M.; Reznikoff, Catherine A.

In: Genes and Development, Vol. 12, No. 2, 15.01.1998, p. 163-174.

Research output: Contribution to journalArticle

Yeager, TR, DeVries, S, Jarrard, DF, Kao, C, Nakada, SY, Moon, TD, Bruskewitz, R, Stadler, WM, Meisner, LF, Gilchrist, KW, Newton, MA, Waldman, FM & Reznikoff, CA 1998, 'Overcoming cellular senescence in human cancer pathogenesis', Genes and Development, vol. 12, no. 2, pp. 163-174.
Yeager TR, DeVries S, Jarrard DF, Kao C, Nakada SY, Moon TD et al. Overcoming cellular senescence in human cancer pathogenesis. Genes and Development. 1998 Jan 15;12(2):163-174.
Yeager, Thomas R. ; DeVries, Sandy ; Jarrard, David F. ; Kao, Chinghai ; Nakada, Stephen Y. ; Moon, Timothy D. ; Bruskewitz, Reginald ; Stadler, Walter M. ; Meisner, Lorraine F. ; Gilchrist, Kennedy W. ; Newton, Michael A. ; Waldman, Frederic M. ; Reznikoff, Catherine A. / Overcoming cellular senescence in human cancer pathogenesis. In: Genes and Development. 1998 ; Vol. 12, No. 2. pp. 163-174.
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