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Carcinogenesis, Vol. 20, No. 11, 2051-2056, November 1999
© 1999 Oxford University Press

Accelerated Papers

Resistance to skin tumorigenesis in DNAPK-deficient SCID mice is not due to immunodeficiency but results from hypersensitivity to TPA-induced apoptosis

Christopher J. Kemp1, Khoa Vo and Kay E. Gurley

Fred Hutchinson Cancer Research Center C1-015, 1100 Fairview Avenue North, PO Box 19024, Seattle, WA 98109-1024, USA

Scid/scid mice have a mutation in the gene encoding the catalytic subunit of DNA-dependent protein kinase (DNAPKcs) and are defective in end joining of DNA double-strand breaks. As a consequence, they are radiosensitive, lack mature T and B lymphocytes and are predisposed to lymphomagenesis. To determine if this DNA repair defect also increased predisposition to skin tumor formation, we treated the dorsal skin of scid/scid mice with the carcinogen 7,12-dimethylbenz[a]anthracene followed by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Contrary to expectations, we observed a 5-fold reduction in skin tumor multiplicity in scid/scid mice. We addressed whether this was related to their immunodeficiency by similarly treating Rag1–/– and Rag2–/– knockout mice which also lack mature T and B lymphocytes. We observed no difference in skin tumor multiplicity for either strain compared with control littermates. This indicates a lack of a significant role for T or B lymphocyte mediated immunity on either papilloma or carcinoma formation. We observed a significant increase in apoptotic and necrotic cell death in follicular and interfollicular epithelial cells of scid/scid mice following TPA treatment. This hypersensitivity of SCID (severe combined immunodeficient) cells to TPA indicates that the resistance to skin tumor formation in scid/scid mice is due to loss of initiated cells through TPA-induced cell killing.

Abbreviations: DMBA, dimethylbenz[a]anthracene; DNAPK, DNA-dependent protein kinase; dsbs, double-stranded breaks; SCID, severe combined immunodeficient; TPA, 12-O-tetradecanoylphorbol-13-acetate.

1 To whom correspondence should be addressed Email: cjkemp{at}fhcrc.org


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