Comparative histomorphometric changes in SENCAR mouse epidermis in response to multiple treatments with complete and stage-specific tumor promoting agents.
Comparative histomorphometric changes in SENCAR mouse epidermis in response to multiple treatments with complete and stage-specific tumor promoting agents.
复制标题
SENCAR 小鼠表皮响应完整和阶段特异性肿瘤促进剂多次治疗的比较组织形态变化。
DOI：
10.1093/carcin/10.10.1855
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发表时间：
1989
期刊：
影响因子：
4.7
通讯作者：
Miller,ML
中科院分区：
文献类型：
--
作者：
Baxter,CS;Andringa,A;Chalfin,K;Miller,ML
多种表皮和真皮细胞对局部应用药物的反应与小鼠多阶段双发育的机制有关。尽管肿瘤表达依赖于多种应用，但这些反应几乎完全是在单一启动子治疗的背景下讨论的。因此，在多次局部应用有效的完全肿瘤促进剂12- o -十四烷醇-13-醋酸酯（TPA）后，记录了角质形成细胞、表皮树突状非角质形成细胞和肾白细胞的反应。为了评估单个细胞类型对促进机制和阶段的反应的重要性，将TPA的反应与在多阶段促进模型的单个阶段具有低完全促进活性但具有显著活性的药物的反应进行了比较。其中包括1期促炎剂4- o -甲基- TPA，作用机制明显不同的2期促炎剂mezerin和正十二烷，以及高度炎性的3期促炎剂苯基丙酸乙酯（EPP）。与先前的研究结果一致，TPA诱导了持续的表皮增生和深色角质形成细胞的增加，尽管EPP和正十二烷也有类似的发现。然而，对十二烷的反应明显延迟，并且对EPP的反应伴随着局灶性表皮破坏和炎症。对十二烷的反应与对甲泽林的反应形成对比，支持了它们的作用机制不同的建议。4-O-methyITPA多次处理未引起暗细胞数量增加，mezerein未引起固缩细胞数量增加，而在单剂量实验的基础上，两种情况下均有增加的预期。在所检测的药物中，只有TPA在没有明显毒性的情况下诱导了苍白树突状表皮细胞的减少，这支持了之前的建议，即对这种细胞类型的长期影响在促进过程中很重要。除4- o -甲基ltpa外，所有药物均观察到一定程度的持续皮肤白细胞浸润，尽管反应程度及其细胞特征似乎强烈依赖于所使用的药物。在TPA的情况下，小核细胞、中性粒细胞和巨噬细胞都对总浸润有重要贡献。在十二烷和EPP中观察到类似的现象，并且TPA没有观察到的嗜酸性粒细胞的额外增加。与TPA和正十二烷不同的是，merzerin仅诱导嗜酸性粒细胞显著增加。如前所述，单次应用TPA可引起形态学改变，并显著减少Thy-1+表皮树突状细胞的数量。
Responses of various cells of the epidermis and dermis to topically applied agents have been implicated in the mechanism of multistage mouse twnorigenesls. These responses have been discussed almost entirely in the context of a single promoter treatment, although tumor expression is dependent on multiple applications. Responses of keratinocytes, epidermal dendritic non-keratinocytes and dennal leukocytes were therefore recorded following multiple topical applications of the potent complete tumor-promoting agent 12-O-tetradecanoylphorbol-13-acetate (TPA). In order to assess the importance of the respoose of individual cell types to the mechanisms and stages of promotion, responses to TPA were compared with those to agents with low complete promoting activity, but significant activity in individual stages of multistage promotion models. These included 4-O-methyl- TPA, a stage 1 promoting agent, mezerein andn-dodecane, stage 2 promoting agents of apparently different mechanism of action, and ethyl phenylpropiolate (EPP), a highly inflammatory stage 3 promoting agent. In agreement with previous findings, TPA induced a persistent epidermal hyperplasia and an increase in dark keratinocytes, although a similar finding was made for EPP andn-dodecane. The response ton-dodecane was significantly delayed, however, and that to EPP was accompanied by focal epidermal destruction and inflammation. The response ton-dodecane contrasted with that found for mezerein, supporting the suggestion that their mechanisms of action are distinct. Multiple treatments of 4-O-methyITPA caused no increase in dark cells, and mezerein induced no increase in numbers of pyknotic cells, whereas increases were expected in both cases on the basis of single dose experiments. Of the agents examined, only TPA induced a decrease in pale dendritic epidermal cells in the absence of marked toxicity, supporting the previous proposal that prolonged effects on this cell type are important in the promotion process. Some degree of persistent dermal leukocyte infiltration was observed with all agents excepting 4-O-methylTPA, although the extent of the response and its cellular characteristics appeared strongly dependent on the agent applied. In the case of TPA small mononuclear cells, neutrophils and macrophages all provided significant contributions to the total infiltrate. A similar phenomenon was observed withn-dodecane and EPP, with an additional increase in eoslnophlls which was not observed with TPA. Merzerein differed from both TPA andn-dodecane in inducing a significant increase only in eosinophils. As reported previously for single applications, prolonged TPA application caused a change in morphology and a considerable decrease in numbers of Thy-1+epidermal dendritic cells.