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

Scid/scid mice have a mutation in the gene encoding the catalytic subunit o f DNA-dependent protein kinase (DNAPK(cs)) and are defective in end joining of DNA double-strand breaks. As a consequence, they are radiosensitive, la ck mature T and B lymphocytes and are predisposed to lymphomagenesis. To de termine if this DNA repair defect also increased predisposition to skin tum or formation, we treated the dorsal skin of scid/scid mice with the carcino gen 7,12-dimethylbenz[a]anthracene followed by the tumor promoter 12-O-tetr adecanoylphorbol-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 R ag1(-/-) and Rag2(-/-) knockout mice which also lack mature T and B lymphoc ytes, We observed no difference in skin tumor multiplicity for either strai n compared with control littermates. This indicates a lack of a significant role for T or B lymphocyte mediated immunity on either papilloma or carcin oma 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 combin ed immunodeficient) cells to TPA indicates that the resistance to skin tumo r formation in scid/scid mice is due to loss of initiated cells through TPA -induced cell killing.