Survivin expression in mouse skin prevents papilloma regression and promotes chemical-induced tumor progression.
Induction of cutaneous squamous cell carcinoma (SCC) in mice, by topical chemical [9,10-dimethylbenzanthracene (DMBA) and phorbol 12-myristate 13-acetate (PMA)] application, is a multistep process involving papilloma formation and progression to carcinoma. We have generated a transgenic (Tg) mouse [keratin-14 (K14)-survivin] with skin expression of survivin, an inhibitor of apoptosis expressed in most human skin cancers and premalignant lesions. K14-survivin mice were resistant to DMBA-induced keratinocyte apoptosis. To investigate the role of survivin and apoptosis in cutaneous carcinogenesis, mice were treated once topically with DMBA followed by twice weekly with PMA for 32 weeks. Surprisingly, tumor formation was less frequent (31% versus 43%) and significantly delayed (P = 0.01) in K14-survivin mice compared with non-Tg littermates. On the other hand, papilloma regression was not observed in Tg mice, whereas 20% of papillomas regressed in non-Tgs; one SCC was generated in Tg mice, whereas none were seen in non-Tgs. To increase tumor formation and SCC in particular, a second experiment was performed with mice on a p53+/- background. Again, DMBA/PMA-induced tumor formation was less (71% versus 89%) and significantly delayed (P = 0.02) in K14-survivin p53+/- animals compared with p53+/- non-Tgs. Papilloma regression was also not observed in Tg p53+/- mice, whereas 10% of papillomas regressed in p53+/- non-Tgs. The rate of papilloma progression to SCC was 21% in Tg p53+/- mice compared with 12% in p53+/- non-Tgs. Papillomas did not reveal significant differences in mitotic or apoptotic indices. Survivin expression was detected in all of the tumors. These results indicate that despite a paradoxical negative effect on tumor formation, survivin expression prevents papilloma regression and promotes conversion to SCC, consistent with its expression in most skin cancers and their precursors.
Allen
Sarah M
SM
Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, USA.
Florell
Scott R
SR
Hanks
Adrianne N
AN
Alexander
April
A
Diedrich
Miyoung J
MJ
Altieri
Dario C
DC
Grossman
Douglas
D
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002273:Carcinogens / Q000633:toxicity; D005260:Female; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000502:physiology*; D009363:Neoplasm Proteins; D010212:Papilloma / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D012867:Skin / Q000187:drug effects / Q000378:metabolism*; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D000077022:Survivin; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology
C107489:BIRC5 protein, human; D002273:Carcinogens; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate