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Overcoming cellular senescence in human cancer pathogenesis
T R Yeager1, S DeVries, D F Jarrard
1Department of Human Oncology, University of Wisconsin Medical School, Madison, Wisconsin 53792 USA.
Genes & Development
|March 7, 1998
Summary
Overcoming cellular senescence via p16 or retinoblastoma protein (pRb) alteration is a critical step in bladder cancer development. Invasive tumors bypass senescence, unlike superficial tumors, indicating key genetic changes drive tumorigenesis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- p16 elevation is observed during senescence in normal human uroepithelial cells (HUC).
- Immortalized HUCs and bladder cancer cell lines exhibit alterations in p16 or retinoblastoma (pRb) tumor suppressor genes.
- Human cancers frequently display p16 or pRb alterations alongside genetic changes associated with immortalization, such as +20q and -3p.
Purpose of the Study:
- To investigate the role of p16 elevation in senescence-induced cell cycle arrest.
- To determine if overcoming p16-mediated senescence is a crucial step in tumorigenesis and in vitro immortalization.
- To analyze p16 and pRb status in transitional cell carcinoma (TCC) biopsies at different stages of tumor progression.
Main Methods:
- Examined p16 and pRb status in primary cultures (P0) and serially passaged in vitro transitional cell carcinoma (TCC) biopsies.
- Utilized comparative genomic hybridization (CGH) to detect chromosomal losses and gains in TCC samples.
- Applied statistical modeling to correlate genetic alterations with tumor characteristics and senescence bypass.
Main Results:
- Superficial TCCs showed elevated p16 and subsequent senescence after limited in vitro passage, similar to normal HUCs.
- Muscle-invasive TCCs presented with pre-existing p16 or pRb alterations at P0 and consistently bypassed senescence.
- Specific chromosomal alterations, including +20q11-q12, +8p22-pter, and -9q, were statistically associated with invasive or superficial TCCs, respectively.
- TP53 mutations were observed in invasive TCCs and linked to genomic instability, but p16 or pRb alterations were more significant predictors of progression.
Conclusions:
- Overcoming senescence, driven by p16 or pRb alterations, is a critical event in human bladder cancer pathogenesis.
- Tumorigenesis and immortalization require at least two genetic changes, which can involve p16/pRb loss combined with other alterations like +20q, -3p, or +8p.
- p16 and pRb alterations are more significant indicators of bladder cancer progression than TP53 mutations.