Voskamp, P. and Bodmann, C. A. and Rebel, H. G. and Koehl, G. E. and Tensen, C. P. and Bavinck, J. N. Bouwes and El Ghalbzouri, A. and Van Kranen, H. J. and Willemze, R. and Geissler, E. K. and De Gruijl, F. R. (2012) Rapamycin impairs UV induction of mutant-p53 overexpressing cell clusters without affecting tumor onset. INTERNATIONAL JOURNAL OF CANCER, 131 (6). pp. 1267-1276. ISSN 0020-7136, 1097-0215
Full text not available from this repository. (Request a copy)Abstract
Because of its antitumor effect, the immunosuppressant rapamycin holds great promise for organ transplant recipients in that it may lower their cancer risk. In a mouse model, we showed previously that rapamycin inhibits the outgrowth of primary skin carcinomas induced by UV radiation. However, the tumors that did grow out showed an altered p53 mutation spectrum. Here, we investigated whether this shift in p53 mutations already occurred in the smallest tumors, which were not affected in onset. We found that rapamycin did not alter the mutational spectrum in small tumors and in preceding microscopic clusters of cells expressing mutant-p53. However, rapamycin did reduce the number of these cell clusters. As this reduction did not affect tumor onset, we subsequently investigated whether rapamycin merely suppressed expression of mutated p53. This was not the case, as we could demonstrate that switching from a diet with rapamycin to one without, or vice versa, did not affect the number of existing mutant-p53 expressing cell clusters. Hence, rapamycin actually reduced the formation of mutant-p53 cell clusters. In wild-type and p53-mutant mice, we could not measure a significant enhancement of UV-induced apoptosis, but we did observe clear enhancement in human skin equivalents. This was associated with a clear suppression of HIF1a accumulation. Thus, we conclude that rapamycin reduces the formation of mutant-p53-expressing cell clusters without affecting tumor onset, suggesting that tumors grow out of a minor subset of cell clusters, the formation of which is not affected by rapamycin.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | SKIN-CANCER; EPIDERMAL-CELLS; MOUSE MODELS; MICE; CARCINOGENESIS; IMMUNOSUPPRESSION; KERATINOCYTES; HIF-1-ALPHA; RECIPIENTS; MUTATIONS; immunosuppressant; rapamycin; p53 mutations; UV carcinogenesis; apoptosis; HIF1a; squamous cell carcinoma; precursor lesions |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Chirurgie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 06 May 2020 05:39 |
| Last Modified: | 06 May 2020 05:39 |
| URI: | https://pred.uni-regensburg.de/id/eprint/18109 |
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