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Review
, 15 (2), 225-33

The Pathology of EMT in Mouse Mammary Tumorigenesis

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Review

The Pathology of EMT in Mouse Mammary Tumorigenesis

Robert Darrell Cardiff. J Mammary Gland Biol Neoplasia.

Abstract

Epithelial-mesenchymal-transition (EMT) tumorigenesis in the mouse was first described over 100 years ago using various terms such as carcinosarcoma and without any comprehension of the underlying mechanisms. Such tumors have been considered artifacts of transplantation and of tissue culture. Recently, EMT tumors have been recognized in mammary glands of genetically engineered mice. This review provides a historical perspective leading to the current status in the context of some of the key molecular biology. The biology of mouse mammary EMT tumorigenesis is discussed with comparisons to human breast cancer.

Figures

Figure 1
Figure 1
Historical. Figure 1 depicts copies of illustrations of mammary “Spindelzollensarkom” from Apolant 1907 (a) “carcinosarcoma” from Dunn 1945 (b), mouse mammary “EMT-type” tumor with immunohistochemical stains for cytokeratin 8/18 (c) and smooth muscle actin (d) from White et al. [47] 2001 and a “triple negative” human breast cancer with undifferentiated cells that stain for vimentin (e) and cytokeratin 8/18 (f). Apolant associated his spindle cell and mixed tumors with transplantation [1]. Dunn associated her mixed tumor with tissue culture and explantation [23]. White found spontaneous EMT-type tumors with loss of the ILK1 transgene and up regulation of Snail [47]. The dual staining, triple negative phenotype in human breast cancer is not recognized as a specific subset or with a specific diagnostic term.
Figure 2
Figure 2
Spindle cell tumor. Figure 2 illustrates the expression of cytokeratin 8/18 detected by immunocytochemistry. Note that the epithelial clusters have the most intense staining pattern. Futhermore, the spindle cell population of fusiform cells with polar cytoplasm also expresses the epithelial antigen. Compare this pattern with staining patterns in Figs. 1 and 3.
Figure 3
Figure 3
Heterogeneity. This panel illustrates some types of heterogeneity found in EMT tumorigenesis. Panels a and b show a subcutaneous EMT tumor from a Tm(p53±xHas±) female. a is stained with hematoxylin and eosin illustrating the spindle cell morphology of EMT tumors. b is stained using immunohistochemistry (IHC) for Cytokeratin 8/18 demonstrating that the spindle cells are uniformly postive of K8/18. The rectangle shown in the thumbnail overviews indicate the approximate area viewed in the high magnification. Compare this pattern with the IHC patterns in the Tg(Myc)-associated EMT tumor in panels C-F. c is stained for K8/18, d for Vimentin, e K14 and f for Smooth Muscle Actin (SMA). Different areas in the tumor have differential staining for each antigen. For example, the densest SMA stain is at the upper tip of the upper sample (f) but K14 staining is more intense around this area (e). This tumor has many tumor giant cells that are lacking in a and b. The scale bar (d) indicates 50 μm magnification of all the higher magnification images. Compare these patterns with the cover illustration that shows well-defined nests of epithelial cells in a sea of spindle cells.
Figure 4
Figure 4
Biology. This panel illustrates the expansile, pushing margin between tumor and host that generally occurs in mouse mammary tumors (a) (image captured at 4×). Compare image 4A with the typical infiltrating margin of an spindle cell EMT-type tumor (b) which infiltrates between the fat cells in the field depicted rather than pushing and compressing the host apidocytes (scale bar is 100 um). Both images depict Tg(Neu) tumors. Image 4A is a Neu-induced primary tumor. Image 4B is a recurrent tumor in a doxycycline-induced Neu host.

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