Mikaelian Igor, Blades Natalie, Churchill Gary A, Fancher Karen, Knowles Barbara B, Eppig Janan T, Sundberg John P
The Jackson Laboratory, Bar Harbor, Maine, USA.
Breast Cancer Res. 2004;6(6):R668-79. doi: 10.1186/bcr930. Epub 2004 Oct 6.
Mammary tumors in mice are categorized by using morphologic and architectural criteria. Immunolabeling for terminal differentiation markers was compared among a variety of mouse mammary neoplasms because expression of terminal differentiation markers, and especially of keratins, provides important information on the origin of neoplastic cells and their degree of differentiation.
Expression patterns for terminal differentiation markers were used to characterize tumor types and to study tumor progression in transgenic mouse models of mammary neoplasia (mice overexpressing Neu (Erbb2), Hras, Myc, Notch4, SV40-TAg, Tgfa, and Wnt1), in spontaneous mammary carcinomas, and in mammary neoplasms associated with infection by the mouse mammary tumor virus (MMTV).
On the basis of the expression of terminal differentiation markers, three types of neoplasm were identified: first, simple carcinomas composed exclusively of cells with a luminal phenotype are characteristic of neoplasms arising in mice transgenic for Neu, Hras, Myc, Notch4, and SV40-TAg; second, 'complex carcinomas' displaying luminal and myoepithelial differentiation are characteristic of type P tumors arising in mice transgenic for Wnt1, neoplasms arising in mice infected by the MMTV, and spontaneous adenosquamous carcinomas; and third, 'carcinomas with epithelial to mesenchymal transition (EMT)' are a characteristic feature of tumor progression in Hras-, Myc-, and SV40-TAg-induced mammary neoplasms and PL/J and SJL/J mouse strains, and display de novo expression of myoepithelial and mesenchymal cell markers. In sharp contrast, EMT was not detected in papillary adenocarcinomas arising in BALB/cJ mice, spontaneous adenoacanthomas, neoplasms associated with MMTV-infection, or in neoplasms arising in mice transgenic for Neu and Wnt1.
Immunohistochemical profiles of complex neoplasms are consistent with a stem cell origin, whereas simple carcinomas might originate from a cell committed to the luminal lineage. In addition, these results suggest that the initiating oncogenic events determine the morphologic features associated with cancer progression because EMT is observed only in certain types of neoplasm.
小鼠乳腺肿瘤通过形态学和结构标准进行分类。对多种小鼠乳腺肿瘤进行终末分化标志物的免疫标记比较，因为终末分化标志物尤其是角蛋白的表达为肿瘤细胞的起源及其分化程度提供了重要信息。
利用终末分化标志物的表达模式来表征肿瘤类型，并研究乳腺肿瘤形成的转基因小鼠模型（过表达Neu（Erbb2）、Hras、Myc、Notch4、SV40-TAg、Tgfa和Wnt1的小鼠）、自发性乳腺癌以及与小鼠乳腺肿瘤病毒（MMTV）感染相关的乳腺肿瘤中的肿瘤进展情况。
基于终末分化标志物的表达，鉴定出三种肿瘤类型：第一，仅由具有管腔表型的细胞组成的单纯癌，是Neu、Hras、Myc、Notch4和SV40-TAg转基因小鼠中发生的肿瘤的特征；第二，显示管腔和肌上皮分化的“复杂癌”，是Wnt1转基因小鼠中发生的P型肿瘤、MMTV感染小鼠中发生的肿瘤以及自发性腺鳞癌的特征；第三，“伴有上皮-间质转化（EMT）的癌”是Hras、Myc和SV40-TAg诱导的乳腺肿瘤以及PL/J和SJL/J小鼠品系中肿瘤进展的特征性表现，并显示肌上皮和间充质细胞标志物的从头表达。形成鲜明对比的是，在BALB/cJ小鼠中发生的乳头状腺癌、自发性棘腺癌、与MMTV感染相关的肿瘤或Neu和Wnt1转基因小鼠中发生的肿瘤中未检测到EMT。
复杂肿瘤的免疫组织化学特征与干细胞起源一致，而单纯癌可能起源于已定向至管腔谱系的细胞。此外，这些结果表明起始致癌事件决定了与癌症进展相关的形态学特征，因为仅在某些类型的肿瘤中观察到EMT。
