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Promoter independence as a feature of most skin papillomas in SENCAR mice
1Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Smithville 78957.
Abstract:
In the present study, the fate of individual papillomas induced by initiation-promotion on the backs of SENCAR mice was monitored after discontinuation of limited promoter treatment. Groups of 40 SENCAR mice each were initiated by a single topical application of 7,12-dimethylbenz[a]anthracene (DMBA) at 2, 1, 0.5, or 0.25 micrograms/mouse. Animals were promoted with 2 micrograms of 12-O-tetradecanoylphorbol-13-acetate (TPA) twice weekly during 10 weeks. At that time point, 10 papilloma bearing mice from each group were randomly selected to follow the growth of their existing tumors. Animals and their individual tumors were identified, charted, and photographed weekly. After an initial increase, the average number of papillomas/mouse remained constant after discontinuation of TPA in all the groups except the group receiving the highest DMBA dose (Group 1) and with highest tumor load. Twenty-one weeks after TPA was discontinued, only 10-20% of the papillomas had regressed and no statistically significant differences were found among the different DMBA dose groups. On the other hand, Group 1 showed the highest percentage of coalescing tumors which was apparently a function of tumor load. In addition, no differences were observed in the proportion of positive tumors with activating point mutations at codon 61 of the Ha-ras gene when comparing samples of papillomas from the highest DMBA initiation dose group (2 micrograms) versus the lowest DMBA initiation dose group (0.25 micrograms). Our present data suggest that papillomas induced with low doses of DMBA in SENCAR mice are no more TPA dependent than those induced by higher initiating doses. Furthermore, in SENCAR mice at the doses used in the present study (0.25-2 micrograms/mouse), the number of so-called "promoter dependent" papillomas represents only a small percentage of the total papillomas produced using the initiation-promotion protocol.
Insights
Papillomas in SENCAR mice, initiated with 7,12-dimethylbenz[a]anthracene (DMBA) and promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA), showed similar regression rates regardless of DMBA dose. Most papillomas were not TPA-dependent after treatment cessation.
Area of Science:
- Carcinogenesis and Chemical Induction of Tumors
- Dermatology and Cutaneous Biology
- Molecular Biology and Genetics
Background:
- Skin papillomas are commonly studied using chemical initiation-promotion models in SENCAR mice.
- Understanding papilloma dependence on promoting agents like 12-O-tetradecanoylphorbol-13-acetate (TPA) is crucial for cancer research.
- The role of initiating carcinogen dose in tumor progression and promoter dependence requires further investigation.
Purpose of the Study:
- To investigate the long-term fate of chemically induced papillomas after discontinuation of promoter treatment.
- To determine if papilloma dependence on 12-O-tetradecanoylphorbol-13-acetate (TPA) varies with the initiating dose of 7,12-dimethylbenz[a]anthracene (DMBA).
- To analyze Ha-ras gene mutations in papillomas induced by different DMBA doses.
Main Methods:
- SENCAR mice were initiated with varying doses of 7,12-dimethylbenz[a]anthracene (DMBA) and promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA).
- Papilloma growth and regression were monitored individually after TPA treatment was stopped.
- Ha-ras gene mutations at codon 61 were analyzed in papilloma samples.
Main Results:
- Papilloma numbers remained stable after TPA discontinuation, except in the highest DMBA dose group with high tumor load.
- Regression rates (10-20%) were similar across different DMBA dose groups 21 weeks post-TPA.
- No significant differences in Ha-ras gene mutations were found between high and low DMBA dose groups, and most papillomas were not TPA-dependent.
Conclusions:
- Papillomas induced by low doses of DMBA in SENCAR mice are not more TPA-dependent than those induced by higher doses.
- The majority of papillomas generated via the initiation-promotion protocol are not dependent on the promoter (TPA) for their continued existence.
- Tumor load, rather than initiating dose, may influence papilloma coalescence.