Induction of invasive mouse skin carcinomas in transgenic mice with mutations in both H-ras and p53
Zhongqiu Zhang1, Ruisheng Yao, Jie Li
1Department of Surgery and The Alvin J. Siteman Cancer Center, Washington University School of Medicine, 660 Euclid Avenue, Box 8109, St. Louis, Missouri 63110, USA.
Abstract:
Synergistic interaction between H-ras and p53 were systematically examined during skin tumorigenesis. Concurrent expression of an activated H-ras gene and a mutant p53 gene was accomplished by crossing p53(Val135/wt) mice with TG.AC mice. Topical application to wild-type mice with benzo(a)pyrene (BaP) alone produced approximately 26% skin tumor incidence, whereas BaP treatment of p53(wt/wt)Hras(TG.AC/wt), p53(Val135/wt)Hras(wt/wt), and p53(Val135/wt)Hras(TG.AC/wt) mice produced a 75%, 77%, and 100% incidence of skin tumors, respectively. An average of 0.33 tumor per mouse was observed in wild-type (p53(wt/wt)Hras(wt/wt)) mice, whereas approximately 1.54, 1.96, and 3.08 tumors per mouse were seen in BaP-treated p53(wt/wt)Hras(TG.AC/wt), p53(Val135/wt)Hras(wt/wt), and p53(Val135/wt)Hras(TG.AC/wt) mice, respectively. The effects on total tumor volume were even more striking with 7-, 48-, and 588-fold increases in tumor volume compared with wild-type (p53(wt/wt)Hras(wt/wt)) in p53(wt/wt)Hras(TG.AC/wt), p53(Val135/wt)Hras(wt/wt), and p53(Val135/wt)Hras(TG.AC/wt) mice, respectively. Histopathologically, all tumors from p53(wt/wt)Hras(wt/wt) mice were either papillomas or well-differentiated squamous cell carcinomas, whereas the tumors in p53(wt/wt)Hras(TG.AC/wt), p53(Val135/wt)Hras(wt/wt), and p53(Val135/wt)Hras(TG.AC/wt) mice were principally squamous cell carcinomas with varying degree of invasiveness. Particularly, tumors in p53(Val135/wt)Hras(TG.AC/wt) mice exhibited the most rapid growth and the extreme form of tumor invasion. Microarray analysis revealed that dominant-negative p53 (Val135) and activated H-ras affected several cellular processes involved in tumorigenesis possibly through its effects on apoptosis, cell cycle arrest, and Ras-mitogen-activated protein kinase pathways. The present study provides the first in vivo evidence that a germ line p53 mutation and activated H-ras act synergistically to profoundly enhance tumor progression.
Insights
This study shows that a mutated p53 gene and an activated H-ras gene work together to significantly accelerate skin tumor development and invasion in mice. These genetic changes profoundly enhance tumor progression, highlighting their synergistic role in tumorigenesis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Skin tumorigenesis is a complex process influenced by genetic mutations.
- The roles of H-ras and p53 in cancer development are well-established but their synergistic interactions require further in vivo investigation.
Purpose of the Study:
- To systematically examine the synergistic interaction between activated H-ras and mutant p53 during skin tumorigenesis.
- To evaluate the impact of combined genetic alterations on tumor incidence, growth, invasion, and molecular pathways.
Main Methods:
- Generation of genetically modified mice co-expressing activated H-ras and mutant p53 (p53Val135/wt).
- Induction of skin tumors using topical application of benzo(a)pyrene (BaP).
- Histopathological analysis and microarray analysis to assess tumor characteristics and molecular changes.
Main Results:
- Concurrent expression of activated H-ras and mutant p53 significantly increased skin tumor incidence, multiplicity, and volume compared to wild-type mice.
- Tumors in mice with both genetic alterations exhibited increased invasiveness and rapid growth.
- Microarray analysis indicated affected apoptosis, cell cycle arrest, and MAPK pathways.
Conclusions:
- A germ line p53 mutation and activated H-ras act synergistically to profoundly enhance skin tumor progression in vivo.
- The combined genetic alterations lead to more aggressive and invasive squamous cell carcinomas.
- This study provides critical in vivo evidence for the cooperative role of p53 and H-ras in driving tumorigenesis.
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