SQUAMOUS-CELL HYPERPLASTIC FOCI - PRECURSORS OF CUTANEOUS PAPILLOMAS INDUCED IN SENCAR MICE BY A 2-STAGE CARCINOGENESIS REGIMEN

We have conducted a series of experiments to characterize the lesions that are precursors of cutaneous papillomas in SENCAR mice initiated w ith 7,12-dimethylbenz(a)anthracene (DMBA) and promoted with 12-O-tetra decanoylphorbol-13-acetate (TPA). The first grossly detectable lesions at sites where papillomas subsequently developed were papules, slight ly raised areas of skin ranging in diameter from 0.25 to similar to 1. 5 mm, Papules were first detected in DMBA-initiated mice 21 days after the start of dosing with TPA. Of 78 DMBA/TPA-induced papules tracked during 15 weeks of TPA treatments, 68% progressed to papillomas, 9% pe rsisted as papules, and 22% completely regressed. Histological evaluat ion of serial sections of 69 DMBA/TPA-induced papules revealed that th ey were focal hyperplastic lesions that we refer to as squamous cell h yperplastic foci (SCHF). These hyperproliferative Lesions appeared to progress through two distinct stages, Stage I SCHF were characterized as regular hyperplastic foci involving the interfollicular epidermis a nd the outer root sheaths of I or more hair follicles down to the leve l of the sebaceous glands. Stage IJ SCHF were foci of irregular epithe lial hyperplasia with increased fibrovascular stroma and involved from 3 to >10 hair follicles; Prominent dilated capillaries and inflammato ry cell infiltrates were frequently associated with both stage I and I I SCHF, Ha-ras gene codon 61 mutations mere detected in 7 of 10 stage I SCHF and 13 of 14 stage II SCHF microdissected from histological sec tions and 7 of 7 of whole papules by mutation-specific FCR analysis, T hese data provide molecular evidence that SCHF are foci of initiated c ells, Further study of these lesions mag contribute to more fully defi ning the sequence of molecular and cellular changes necessary for tumo rigenesis in mouse skin. SCHF mag also have utility as early indicator s of potential skin tumorigenicity in cancer bioassays.