Binder R L, Johnson G R, Gallagher P M, Stockman S L, Sundberg J P, Conti C J
The Procter & Gamble Company, Miami Valley Laboratories, Cincinnati, Ohio 45253-8707, USA.
Cancer Res. 1998 Oct 1;58(19):4314-23.
We have conducted a series of experiments to characterize the lesions that are precursors of cutaneous papillomas in SENCAR mice initiated with 7,12-dimethylbenz(a)anthracene (DMBA) and promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA). The first grossly detectable lesions at sites where papillomas subsequently developed were papules, slightly raised areas of skin ranging in diameter from 0.25 to approximately 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% persisted as papules, and 22% completely regressed. Histological evaluation of serial sections of 69 DMBA/TPA-induced papules revealed that they were focal hyperplastic lesions that we refer to as squamous cell hyperplastic 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 and the outer root sheaths of 1 or more hair follicles down to the level of the sebaceous glands. Stage II SCHF were foci of irregular epithelial hyperplasia with increased fibrovascular stroma and involved from 3 to >10 hair follicles. Prominent dilated capillaries and inflammatory cell infiltrates were frequently associated with both stage I and II SCHF. Ha-ras gene codon 61 mutations were detected in 7 of 10 stage I SCHF and 13 of 14 stage II SCHF microdissected from histological sections and 7 of 7 of whole papules by mutation-specific PCR analysis. These data provide molecular evidence that SCHF are foci of initiated cells. Further study of these lesions may contribute to more fully defining the sequence of molecular and cellular changes necessary for tumorigenesis in mouse skin. SCHF may also have utility as early indicators of potential skin tumorigenicity in cancer bioassays.
我们进行了一系列实验，以表征在经7,12 - 二甲基苯并(a)蒽（DMBA）启动并用12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯（TPA）促进的SENCAR小鼠中，作为皮肤乳头状瘤前体的病变。在随后发生乳头状瘤的部位，最初可通过肉眼检测到的病变是丘疹，即皮肤略微隆起的区域，直径范围为0.25至约1.5毫米。丘疹在开始用TPA给药后21天在DMBA启动的小鼠中首次被检测到。在TPA治疗的15周内追踪的78个DMBA/TPA诱导的丘疹中，68%进展为乳头状瘤，9%持续为丘疹，22%完全消退。对69个DMBA/TPA诱导的丘疹的连续切片进行组织学评估显示，它们是局灶性增生性病变，我们将其称为鳞状细胞增生灶（SCHF）。这些过度增殖性病变似乎经历两个不同阶段。I期SCHF的特征是规则的增生灶，涉及毛囊间表皮和1个或更多毛囊的外根鞘直至皮脂腺水平。II期SCHF是不规则上皮增生灶，伴有纤维血管基质增加，涉及3至>10个毛囊。显著扩张的毛细血管和炎性细胞浸润经常与I期和II期SCHF相关。通过突变特异性PCR分析，在从组织学切片显微切割的10个I期SCHF中的7个、14个II期SCHF中的13个以及7个完整丘疹中的7个中检测到Ha - ras基因密码子61突变。这些数据提供了分子证据，表明SCHF是起始细胞的病灶。对这些病变的进一步研究可能有助于更全面地确定小鼠皮肤肿瘤发生所需的分子和细胞变化序列。SCHF也可能作为癌症生物测定中潜在皮肤致瘤性的早期指标。
