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Diet and cancer prevention studies in p53-deficient mice
S D Hursting1, S N Perkins, J M Phang
1National Cancer Institute, Bethesda, MD 20892,USA. hursting@ncifcrf.gov
Abstract:
Progress in mechanism-based cancer prevention research may be facilitated by the use of animal models displaying specific genetic susceptibilities for cancer such as mice deficient in the p53 tumor suppressor gene, the most frequently altered gene in human cancer. We observed in p53-knockout (p53-/-) mice that calorie restriction (CR; 60% of the control group's intake of carbohydrate energy) increased the latency of spontaneous tumor development (mostly lymphomas) approximately 75%, decreased serum insulin-like growth factor (IGF)-1 and leptin levels, significantly slowed thymocyte cell cycle traverse and induced apoptosis in immature thymocytes. In heterozygous p53-deficient (p53+/-) mice, CR and 1 d/wk of food deprivation each significantly delayed spontaneous tumor development (a mix of lymphomas, sarcomas and epithelial tumors) and decreased serum IGF-1 and leptin levels even when begun late in life. We have also developed a rapid and relevant p53+/- mouse mammary tumor model by crossing p53-deficient mice with MMTV-Wnt-1 transgenic mice, and found that CR and 1 d/wk food deprivation significantly increased mammary tumor latency (greater than twofold) and reduced the mean serum IGF-1 and leptin levels to <50% of that of control mice (P < 0.0001). In addition, fluasterone, fenretinide and soy each delayed tumor development but had little effect on IGF-1 or leptin levels. We have capitalized on the susceptibility of p53+/- mice to chronic, low dose, aromatic amine-induced bladder carcinogenesis to develop a useful model for evaluating bladder cancer prevention approaches such as cyclooxygenase-2 inhibition. As demonstrated by these examples, mice with specific (and human-like) genetic susceptibilities for cancer provide powerful new tools for testing and characterizing interventions that may inhibit the process of carcinogenesis in humans.
Insights
Calorie restriction and food deprivation significantly delay tumor development in mice with p53 gene mutations, offering insights into cancer prevention strategies. These interventions also reduced key growth factors like insulin-like growth factor-1 (IGF-1) and leptin.
Area of Science:
- Oncology
- Genetics
- Nutritional Science
Background:
- The p53 tumor suppressor gene is frequently altered in human cancers.
- Animal models with specific genetic susceptibilities, like p53-deficient mice, are crucial for cancer prevention research.
- Understanding the mechanisms of cancer development and prevention is essential for human health.
Purpose of the Study:
- To investigate the effects of calorie restriction (CR) and food deprivation on spontaneous tumor development in p53-deficient mice.
- To evaluate the impact of these dietary interventions on serum levels of insulin-like growth factor-1 (IGF-1) and leptin.
- To establish and utilize genetically susceptible mouse models for testing cancer prevention strategies.
Main Methods:
- Utilized p53-knockout (p53-/-) and heterozygous p53-deficient (p53+/-) mice.
- Administered calorie restriction (60% of control intake) and intermittent food deprivation (1 day/week).
- Developed a p53+/- mouse mammary tumor model by crossing with MMTV-Wnt-1 transgenic mice.
- Assessed tumor development latency, serum IGF-1 and leptin levels, thymocyte cell cycle, and apoptosis.
- Used p53+/- mice for evaluating bladder carcinogenesis prevention with cyclooxygenase-2 inhibition.
Main Results:
- Calorie restriction increased tumor latency by approximately 75% in p53-/- mice, decreasing serum IGF-1 and leptin.
- CR and food deprivation significantly delayed tumor development in p53+/- mice, even when initiated late in life.
- In a p53+/- mammary tumor model, CR and food deprivation more than doubled mammary tumor latency and reduced serum IGF-1 and leptin.
- Fluasterone, fenretinide, and soy also delayed tumor development but had minimal impact on IGF-1 or leptin levels.
Conclusions:
- Mice with human-like genetic susceptibilities for cancer are valuable tools for testing cancer prevention interventions.
- Calorie restriction and food deprivation show promise as strategies to inhibit carcinogenesis.
- These models facilitate the characterization of interventions targeting cancer development mechanisms.