Analysis of the ability of 12-O-tetradecanoylphorbol-13-acetate to induce epidermal hyperplasia, transforming growth factor-alpha, and skin tumor promotion in wa-1 mice.
Wa-1 mutant mice possess a defect in the production of transforming growth factor-alpha (TGF-alpha) that leads to a phenotype characterized by wavy hair and curly whiskers. In light of recent evidence indicating the importance of TGF-alpha in epithelial tumorigenesis, this study characterizes the responsiveness of wa-1 mice to skin tumor promotion by the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA). The responsiveness of wa-1 mice to TPA was compared with that of SENCAR and C57BL/6 mice, representing mouse lines highly sensitive and resistant to skin tumor promotion, respectively. Wa-1 mice were found to be very resistant to skin tumor promotion by TPA after initiation with 10 nmol DMBA, similar to C57BL/6 mice. TPA failed to induce a dramatic increase in TGF-alpha mRNA and protein in the skin of wa-1 mice, whereas TGF-alpha mRNA and protein were dramatically induced in the skin (both epidermis and dermis) of SENCAR and C57BL/6 mice. TPA treatment dramatically increased mRNA levels of two other EGF receptor ligands, amphiregulin and heparin binding-EGF, however, in the skin of all three mouse lines. Comparison of histologic changes in skin revealed that wa-1 mice exhibited only modest sustained epidermal hyperplasia after multiple treatments with TPA, similar in magnitude to that of C57BL/6 mice and significantly lower than that of SENCAR mice. The current data indicate that wa-1 mice are relatively resistant to TPA promotion. Possible mechanisms for this resistance are discussed.
Kiguchi
K
K
The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville 78957, USA.
Beltrán
L
L
Dubowski
A
A
DiGiovanni
J
J
D066258:Amphiregulin; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology*; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000378:metabolism; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D006133:Growth Substances / Q000378:metabolism; D006493:Heparin / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D006965:Hyperplasia / Q000139:chemically induced; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL / Q000502:physiology; D018632:Mice, Inbred SENCAR; D008817:Mice, Mutant Strains / Q000502:physiology*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D012867:Skin / Q000473:pathology*; D012878:Skin Neoplasms / Q000139:chemically induced*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis* / Q000235:genetics
D066258:Amphiregulin; D000970:Antineoplastic Agents; C587849:Areg protein, mouse; D002273:Carcinogens; D066255:EGF Family of Proteins; D006023:Glycoproteins; D006133:Growth Substances; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; D004815:Epidermal Growth Factor; D006493:Heparin; D013755:Tetradecanoylphorbol Acetate